WO2023177250A1 - Novel heterocyclic inhibitor for histone deacetylase, and pharmaceutical composition comprising same - Google Patents

Novel heterocyclic inhibitor for histone deacetylase, and pharmaceutical composition comprising same Download PDF

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WO2023177250A1
WO2023177250A1 PCT/KR2023/003562 KR2023003562W WO2023177250A1 WO 2023177250 A1 WO2023177250 A1 WO 2023177250A1 KR 2023003562 W KR2023003562 W KR 2023003562W WO 2023177250 A1 WO2023177250 A1 WO 2023177250A1
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compound
indazole
carboxylic acid
acid hydroxyamide
disease
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PCT/KR2023/003562
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French (fr)
Korean (ko)
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전라옥
미스라찬드라부산
김지수
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숙명여자대학교산학협력단
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Priority claimed from KR1020230034303A external-priority patent/KR20230136060A/en
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Publication of WO2023177250A1 publication Critical patent/WO2023177250A1/en

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to a novel heterocyclic compound having the ability to inhibit histone deacetylase enzymes and its medical use.
  • it relates to a more selective and effective HDAC6 inhibitor and histone deacetylator among histone deacetylase (HDAC) enzymes. It relates to the treatment of enzyme-related diseases.
  • Histone deacetylase plays an important role in gene expression and differentiation and maintaining cell homeostasis by promoting the process of removing acetylation groups from acetylated 3-amino lysine residues of histone and non-histone proteins.
  • HDACs are organized into four classes and 18 subtypes: class I (HDAC1, 2, 3, and 8), class II (HDAC4, 5, 7, 9, 6, and 10), class III (SIRT1-7), and class IV. Each is classified as (HDAC11).
  • HDACs belonging to Class I, II and IV are Zn 2+ -dependent enzymes, whereas Class III HDACs are characterized as nicotinamide adenine dinucleotide (NAD)-dependent enzymes.
  • NAD nicotinamide adenine dinucleotide
  • HDAC6 consists of 1215 amino acid residues, including CD1 and CD2 catalytic domains in the N-terminal and central regions, respectively.
  • the C-terminus contains a zinc-finger ubiquitin binding domain that promotes the interaction between the ubiquitin proteasome and aggresome pathways.
  • HDAC6 also induces deacetylation using non-histone proteins such as ⁇ -tubulin, cortactin, tau, peroxiredoxin, and heat shock protein (HSP90) as substrates.
  • non-histone proteins such as ⁇ -tubulin, cortactin, tau, peroxiredoxin, and heat shock protein (HSP90) as substrates.
  • HDAC6 is involved in various physiological processes such as cell migration, autophagy, endocytosis, protein transport, apoptosis, and degradation, and has these important physiological functions. Because of this, HDAC6 has become an effective therapeutic target for various human diseases such as cancer, inflammation, and immune disorders.
  • HDAC inhibitors have been researched and developed, and five types of FDA-approved HDAC inhibitory anticancer drugs are in use.
  • these drugs are non-selective HDAC inhibitors, and there is a need to develop selective inhibitors targeting characteristic isoforms with reduced side effects.
  • the similarity between HDAC subtypes is large, so discovering subtype-selective inhibitors is not an easy task, but there is a high demand for the development of more selective and effective HDAC6 inhibitors.
  • the purpose of the present invention is to provide a novel HDAC6 inhibitor.
  • Another object of the present invention is to provide a method of inhibiting HDAC6 using the novel HDAC6 inhibitor.
  • Another purpose of the present invention is to provide a treatment for HDAC6-related diseases through discovery of new HDAC6 inhibitors.
  • Another object of the present invention is to provide a method of treating HDAC6-related diseases, including the step of administering a novel HDAC6 inhibitor to a subject in need of treatment for HDAC6-related diseases.
  • the present invention provides a compound selected from the compounds represented by the following formula (1) or pharmaceutically acceptable salts thereof:
  • X is selected from hydrogen, fluorine, chlorine or bromine
  • A is selected from substituted or unsubstituted phenyl, naphthyl or heterocyclic compounds,
  • substitution is one or more substituents selected from (C1 ⁇ C10)alkyl, (C1 ⁇ C10)alkoxy, halo, difluoromethyl, trifluoromethyl, hydroxy, cyano, nitro, phenyl, benzyloxy, or phenoxy. is replaced with,
  • the heterocyclic compound is a 5- or 6-ring heteroaryl compound
  • n is an integer from 1 to 3.
  • the present invention provides a pharmaceutical composition for the treatment or prevention of diseases related to histone deacetylase 6 (HDAC6), comprising a compound selected from the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
  • HDAC6 histone deacetylase 6
  • the present invention provides a health functional food for improving or preventing diseases related to histone deacetylase 6 (HDAC6), comprising a compound selected from the compounds represented by Formula 1 or pharmaceutically acceptable salts thereof. do.
  • HDAC6 histone deacetylase 6
  • the present invention provides a composition for inhibiting histone deacetylase 6 (HDAC6) comprising a compound selected from the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
  • HDAC6 histone deacetylase 6
  • the present invention provides a method of inhibiting histone deacetylase 6 (HDAC6), which includes the step of treating a compound selected from the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
  • HDAC6 histone deacetylase 6
  • the present invention includes the step of administering a compound selected from the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof to a subject suffering from a disease related to histone deacetylase 6 (HDAC6).
  • HDAC6 histone deacetylase 6
  • the present invention relates to a novel heterocyclic histone deacetylase inhibitor.
  • it provides a more selective and effective HDAC6 inhibitor for HDAC6 among histone deacetylase (HDAC) enzymes, thereby treating HDAC6-related diseases, such as cancer.
  • HDAC histone deacetylase
  • it is possible to develop treatments for various diseases such as inflammatory diseases, autoimmune diseases, fibrotic diseases, and degenerative diseases.
  • the present inventor synthesized a new indazole-based HDAC6 inhibitor and completed the present invention by confirming its excellent HDAC6 inhibitory activity.
  • the present invention provides a compound selected from the compounds represented by the following formula (1) or pharmaceutically acceptable salts thereof:
  • X is selected from hydrogen, fluorine, chlorine or bromine
  • A is selected from substituted or unsubstituted phenyl, naphthyl or heterocyclic compounds,
  • substitution is one or more substituents selected from (C1 ⁇ C10)alkyl, (C1 ⁇ C10)alkoxy, halo, difluoromethyl, trifluoromethyl, hydroxy, cyano, nitro, phenyl, benzyloxy, or phenoxy. is replaced with,
  • the heterocyclic compound is a 5- or 6-ring heteroaryl compound
  • n may be an integer from 1 to 3.
  • the heterocyclic compound may be selected from the group consisting of thiophene, furan, pyrazole, pyridine, pyran, oxazine, thiazine, pyrimidine, and piperazine, but is not limited thereto.
  • the compound may be a compound represented by the following formula 1-1:
  • X is hydrogen or fluorine
  • A is selected from phenyl, naphthyl or pyrimidyl
  • R 1 and R 2 may each be the same or different and are selected from hydrogen, (C1 ⁇ C4)alkyl, (C1 ⁇ C4)alkoxy, halo, difluoromethyl, trifluoromethyl, phenyl, benzyloxy, or phenoxy.
  • n may be an integer from 1 to 3.
  • the compound is i) A is selected from phenyl, naphthyl or pyrimidyl, and R 1 is hydrogen, (C1 ⁇ C4)alkyl, (C1 ⁇ C4)alkoxy, halo, difluoromethyl, tri It is selected from fluoromethyl, phenyl, benzyloxy or phenoxy, R 2 is selected from hydrogen, (C1 ⁇ C4)alkoxy or halo, and n may be an integer of 1 to 2.
  • the compound is 2-Benzyl-2 H -indazole-6-carboxylic acid hydroxyamide (Compound 50 ); 2-(4 - Methoxybenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 51); 2-(4 - Methylbenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 52); 2-(4 - Fluorobenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 53); 2-(4 - Chlorobenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 54); 2-(4 - Bromobenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 55); 2-(3 - Trifluoromethoxybenzyl) -2H- indazole-6-carboxylic acid hydroxyamide (Compound 56); 2-(4
  • the compound according to the present invention can more selectively inhibit histone deacetylase 6 (HDAC6).
  • HDAC6 histone deacetylase 6
  • the ‘pharmaceutically acceptable salt’ may be used in the form of either a pharmaceutically acceptable basic salt or an acidic salt.
  • Basic salts can be used in the form of either organic base salts or inorganic base salts, such as sodium salts, potassium salts, calcium salts, lithium salts, magnesium salts, cesium salts, aminium salts, and ammonium salts. , triethylaminium salt, pyridinium salt, etc. can be used, but are not limited thereto.
  • an acid addition salt formed by a free acid is useful as the acid salt.
  • Inorganic acids and organic acids can be used as free acids.
  • Hydrochloric acid, hydrobromic acid, sulfuric acid, sulfurous acid, and phosphoric acid can be used as inorganic acids, and citric acid, acetic acid, maleic acid, fumaric acid, gluconic acid, and methanesulfonic acid can be used as organic acids.
  • benzenesulfonic acid camphorsulfonic acid, oxalic acid, malonic acid, glutaric acid, acetic acid, glyconic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, citric acid, aspartic acid. etc.
  • hydrochloric acid can be used as the inorganic acid
  • methanesulfonic acid can be used as the organic acid.
  • the compound according to the present invention may include not only pharmaceutically acceptable salts, but also all salts, hydrates, and solvates that can be prepared by conventional methods.
  • the addition salt according to the present invention can be prepared by conventional methods.
  • the compound is dissolved in a water-miscible organic solvent, such as acetone, methanol, ethanol, or acetonitrile, and an excess amount of organic base is added or an inorganic base is added.
  • a water-miscible organic solvent such as acetone, methanol, ethanol, or acetonitrile
  • an excess amount of organic base is added or an inorganic base is added.
  • It can be prepared by adding an aqueous solution of a base and then precipitating or crystallizing it.
  • an addition salt can be obtained by evaporating the solvent or excess base from this mixture and drying it, or it can be prepared by suction filtration of the precipitated salt.
  • the present invention provides a pharmaceutical composition for the treatment or prevention of diseases related to histone deacetylase 6 (HDAC6), comprising a compound selected from the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
  • HDAC6 histone deacetylase 6
  • the present invention includes the step of administering a compound selected from the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof to a subject suffering from a disease related to histone deacetylase 6 (HDAC6).
  • HDAC6 histone deacetylase 6
  • the histone deacetylase 6 (HDAC6)-related disease may be selected from the group consisting of cancer disease, inflammatory disease, autoimmune disease, fibrotic disease, and degenerative disease.
  • the above cancer diseases include colon cancer, lung cancer, kidney cancer, bladder cancer, liver cancer, thymus cancer, ovarian cancer, cervical cancer, breast cancer, colon cancer, stomach cancer, pancreas cancer, colon cancer, peritoneal metastasis, skin cancer, bladder cancer, prostate cancer, osteosarcoma, and fibrous cancer. It may be selected from the group consisting of tumor, brain tumor, acute lymphoblastic leukemia, acute myeloid leukemia, lymphoma, and neuroblastoma, but is not limited thereto.
  • the inflammatory or autoimmune diseases include osteoarthritis, rheumatoid arthritis, dermatitis, allergy, atopy, asthma, psoriasis, conjunctivitis, rhinitis, otitis media, pharyngitis, tonsillitis, pneumonia, gastric ulcer, gastritis, Crohn's disease, and inflammatory bowel disease ( inflammatory bowel disease, lupus, hepatitis, cystitis, interstitial cystitis, nephritis, Sjogren's syndrome, multiple sclerosis, Hashimoto thyroiditis, polymyositis, scleroderma, Addison disease ), vitiligo, pernicious anemia, cystic fibrosis, graft-versus-host disease, transplant rejection disease, autoimmune diabetes, diabetic retinopathy retinopathy, ischemia-reperfusion injury, Post-angioplasty restenosis, Chronic obstructive pulmonary disease (COPD), Grave
  • the fibrotic disease may be selected from the group consisting of pulmonary fibrosis, renal fibrosis, cardiac fibrosis, liver fibrosis, scleroderma, skeletal muscle fibrosis, and diabetic fibrosis, but is not limited thereto.
  • liver fibrosis may include, but is not limited to, nonalcoholic steatohepatitis (NASH) or nonalcoholic fatty liver disease (NAFLD).
  • NASH nonalcoholic steatohepatitis
  • NAFLD nonalcoholic fatty liver disease
  • the degenerative disease is selected from the group consisting of stroke, paralysis, memory loss, memory impairment, dementia, amnesia, Parkinson's disease, Alzheimer's disease, Pick's disease, Creutzfeld-Jakob disease, Huntington's disease, and Lou Gehrig's disease. It may be a degenerative neurological disease, but it is not limited to this.
  • the pharmaceutical composition may be provided in one or more formulations selected from the group consisting of gels, emulsions, injections, powders, granules, aerosols, pastes, transdermal absorbents, and patches according to conventional methods, but is not limited thereto.
  • the pharmaceutical composition includes suitable carriers, excipients, disintegrants, sweeteners, coating agents, swelling agents, lubricants, lubricants, flavoring agents, antioxidants, buffers, and bacteriostatic agents commonly used in the preparation of pharmaceutical compositions. , it may further include one or more additives selected from the group consisting of diluents, dispersants, surfactants, binders, and lubricants.
  • carriers, excipients, and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, and microcrystalline.
  • Cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil can be used.
  • Solid preparations for oral administration include tablets, pills, powders, granules, and capsules.
  • Such solid preparations can be prepared by mixing the composition with at least one or more excipients, such as starch, calcium carbonate, sucrose or lactose, gelatin, etc.
  • excipients such as starch, calcium carbonate, sucrose or lactose, gelatin, etc.
  • lubricants such as magnesium styrate and talc can also be used.
  • Liquid preparations for oral use include suspensions, oral solutions, emulsions, and syrups.
  • various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included.
  • Preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, etc.
  • Non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate.
  • injectable ester such as ethyl oleate.
  • As a base for suppositories witepsol, macrogol, tween 61, cacao, laurin, glycerogeratin, etc. can be used.
  • the pharmaceutical composition may be administered to the subject in a conventional manner via intravenous, intraarterial, intraperitoneal, intramuscular, intraarterial, intraperitoneal, intrasternal, transdermal, intranasal, inhalation, topical, rectal, oral, intraocular or intradermal routes. It can be administered.
  • the preferred dosage of the compound may vary depending on the subject's condition and weight, type and degree of disease, drug form, administration route and period, and may be appropriately selected by a person skilled in the art. According to one embodiment of the present invention, but is not limited thereto, the daily dosage may be 0.01 to 200 mg/kg, specifically 0.1 to 200 mg/kg, and more specifically 0.1 to 100 mg/kg. Administration may be administered once a day or may be divided into several administrations, and the scope of the present invention is not limited thereby.
  • the 'subject' may be a mammal, including humans, but is not limited to these examples.
  • the present invention provides a health functional food for improving or preventing diseases related to histone deacetylase 6 (HDAC6), comprising a compound selected from the compounds represented by Formula 1 or pharmaceutically acceptable salts thereof. do.
  • HDAC6 histone deacetylase 6
  • health functional food refers to food manufactured and processed using raw materials or ingredients with functionality useful to the human body in accordance with the Health Functional Food Act, and "functional” refers to food that is related to the structure and function of the human body. It means ingestion for the purpose of controlling nutrients or obtaining useful health effects such as physiological effects.
  • the above-mentioned health functional food may contain ordinary food additives, and the suitability of the above-mentioned “food additive” is determined in accordance with the general provisions of the Food Additive Code and General Test Methods approved by the Ministry of Food and Drug Safety, unless otherwise specified. It is determined in accordance with the relevant standards and standards.
  • Items listed in the "Food Additives Code” include, for example, chemical compounds such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid; natural additives such as subchromic pigment, licorice extract, crystalline cellulose, high-liquid pigment, and guar gum; Examples include mixed preparations such as sodium L-glutamate preparations, noodle additive alkaline preparations, preservative preparations, and tar coloring preparations.
  • the effective dose of the active ingredient contained in the health functional food may be used in accordance with the effective dose of the therapeutic agent, but in the case of long-term intake for the purpose of health and hygiene or health control, it may be below the above range. , It is certain that the active ingredient can be used in amounts exceeding the above range because there is no problem in terms of safety.
  • the present invention provides a composition for inhibiting histone deacetylase 6 (HDAC6) comprising a compound selected from the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
  • HDAC6 histone deacetylase 6
  • the present invention provides a method of inhibiting histone deacetylase 6 (HDAC6), which includes the step of treating a compound selected from the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
  • HDAC6 histone deacetylase 6
  • the composition can be used as a pharmaceutical composition, health functional food, reagent composition, etc.
  • Indazole derivatives as HDAC6 inhibitors were synthesized by the general process according to Scheme 1, Scheme 2, or Scheme 3 below. The specific synthesis process will be described in detail for each compound later.
  • Carboxylic acid derivatives (Compound 26-49 and Compound 75; 1 mmol), hydroxyamine hydrochloride (3 mmol), BOP (benzotriazol-l-yl-oxy-tris-(dimethylamino)phosphonium hexa-fluorophosphate; 1.7 mmol) and A mixture of diisopropylethylamine (DIPEA; 3 mmol) was added to DMSO (5-10 ml) and stirred at room temperature for 6-8 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The product was purified by column chromatography using chloroform:methanol (90:10) as an eluent.
  • DIPEA diisopropylethylamine
  • N2- substituted 5-fluoro- 2H -indazole-6-carboxylic acid methyl ester (compound 82-84, 0.34 mmol) was dissolved in methanol (1 ml) and THF (1 ml) and added to 2N NaOH solution ( 0.5 ml) was added slowly. The reaction mixture was stirred at room temperature for 2 hours, added to water, neutralized with 2N HCl, and the precipitate was filtered and dried to obtain carboxylic acid derivatives (compounds 85 - 87).
  • Carboxylic acid derivatives (compounds 85 - 87; 0.27 mmol), hydroxyamine hydrochloride (0.82 mmol), benzotriazol-l-yl-oxy-tris-(dimethylamino)phosphonium hexa-fluorophosphate (BOP; 0.41 mmol) and diisopropylethylamine (DIPEA) ; 0.82 mmol) was added to DMSO (1 - 2 ml) and stirred at room temperature for 6-8 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The product was purified by column chromatography using chloroform:methanol (90:10) as an eluent.
  • 2X HDAC enzyme was dispensed into each well of the reaction plate except for the control well without HDAC enzyme, and buffer was dispensed into the control well without enzyme.
  • Acoustic technology Echo550, nanoliter range
  • compounds dissolved in 100% DMSO were added to the enzyme mixture, spun down, and preincubated for 10 minutes at room temperature.
  • 2X substrate mixture Fluorogenic HDAC substrate
  • HDAC6 was incubated at 30°C for 1 hour
  • HDAC8 was incubated for 2 hours.
  • SPA3602, 3603, 3606, 3608, 3610, 3612, 3614, 3616, 3618, 3620, 3621, 3622, 3624, 3626, 3628, 3630, 3632, 3634 , 3636, 3638, 3640, 3642, 3644, 3646 and 3648 showed effective inhibitory activity against HDAC6, with IC 50 in the range of 1.3 to 29.3 nM as shown in the following table, and for HDAC8, IC 50 in the range of 500.3 to 8392.0 nM.
  • HDAC6 selectivity was confirmed by showing relatively low activity. From these results, it was confirmed that the N2 -substituted derivative is a selective and effective inhibitor of HDAC6, and can be used as a treatment for various diseases such as cancer diseases, inflammatory diseases, autoimmune diseases, and fibrotic diseases.
  • a powder was prepared by mixing 20 mg of compound 50 (SPA3602), 100 mg of lactose, and 10 mg of talc and filling it in an airtight bubble.
  • Tablets were prepared by mixing 10 mg of compound 50 (SPA3602), 100 mg of corn starch, 100 mg of lactose, and 2 mg of magnesium stearate and compressing them according to a conventional tablet manufacturing method.
  • a capsule was prepared by mixing 10 mg of Compound 50 (SPA3602), 100 mg of corn starch, 100 mg of lactose, and 2 mg of magnesium stearate, mixing the above ingredients according to a typical capsule manufacturing method, and filling a gelatin capsule.
  • Compound 50 1 mg, appropriate amount of vitamin mixture (vitamin A acetate 70 ⁇ g, vitamin E 1.0 mg, vitamin B1 0.13 mg, vitamin B2 0.15 mg, vitamin B6 0.5 mg, vitamin B12 0.2 ⁇ g, vitamin C10 mg, biotin 10 ⁇ g , nicotinic acid amide 1.7 mg, folic acid 50 ⁇ g, calcium pantothenate 0.5 mg) and mineral mixture (ferrous sulfate 1.75 mg, zinc oxide 0.82 mg, magnesium carbonate 25.3 mg, monobasic potassium phosphate 15 mg, dicalcium phosphate 55 mg) , 90 mg of potassium citrate, 100 mg of calcium carbonate, and 24.8 mg of magnesium chloride) were mixed to prepare granules, and health food was prepared according to a conventional method.
  • vitamin mixture vitamin A acetate 70 ⁇ g, vitamin E 1.0 mg, vitamin B1 0.13 mg, vitamin B2 0.15 mg, vitamin B6 0.5 mg, vitamin B12 0.2 ⁇ g, vitamin C10 mg,

Abstract

The present invention relates to a novel heterocyclic inhibitor for histone deacetylase (HDAC), a novel therapeutic agent for HDAC-associated diseases, and a pharmaceutical composition comprising same. More specifically, a compound according to the present invention exhibits a more selective and effective inhibitory activity with respect to HDAC6 even from among HDACs, and thus can be effectively used as a therapeutic agent for various HDAC6-associated diseases such as cancer, inflammatory diseases, autoimmune diseases, fibrotic diseases and degenerative diseases.

Description

신규 헤테로고리 히스톤 탈아세틸화 효소 저해제 및 이를 포함하는 약학조성물Novel heterocyclic histone deacetylase inhibitor and pharmaceutical composition containing the same
본 발명은 히스톤 탈아세틸화 효소 저해능을 갖는 신규 헤테로고리 화합물 및 이의 의학적 용도에 관한 것으로, 특히 히스톤 탈아세틸화 효소(Histone deacetylase; HDAC) 중에서도 HDAC6에 대해 보다 선택적이고 효과적인 HDAC6 저해제 및 히스톤 탈아세틸화 효소 관련 질환의 치료에 관한 것이다.The present invention relates to a novel heterocyclic compound having the ability to inhibit histone deacetylase enzymes and its medical use. In particular, it relates to a more selective and effective HDAC6 inhibitor and histone deacetylator among histone deacetylase (HDAC) enzymes. It relates to the treatment of enzyme-related diseases.
히스톤 탈아세틸화 효소(Histone deacetylase; HDAC)는 히스톤 및 비히스톤 단백질의 아세틸화된 3-아미노 리신 잔기로부터 아세트기가 제거되는 과정을 촉진함으로써 유전자의 발현 및 분화, 세포의 항상성 유지에 중요한 역할을 수행한다. HDAC은 네 개의 클래스와 18개의 아형으로 구성되어 클래스 I (HDAC1, 2, 3 및 8), 클래스 II (HDAC4, 5, 7, 9, 6 및 10), 클래스 III (SIRT1-7) 및 클래스 IV (HDAC11)로 각기 분류된다. Class I, II 및 IV에 속하는 HDAC은 Zn2+ 의존성 효소인 반면, Class III HDAC는 니코틴아미드 아데닌 디뉴클레오티드(NAD) 의존성 효소로 특징지어진다. Histone deacetylase (HDAC) plays an important role in gene expression and differentiation and maintaining cell homeostasis by promoting the process of removing acetylation groups from acetylated 3-amino lysine residues of histone and non-histone proteins. do. HDACs are organized into four classes and 18 subtypes: class I (HDAC1, 2, 3, and 8), class II (HDAC4, 5, 7, 9, 6, and 10), class III (SIRT1-7), and class IV. Each is classified as (HDAC11). HDACs belonging to Class I, II and IV are Zn 2+ -dependent enzymes, whereas Class III HDACs are characterized as nicotinamide adenine dinucleotide (NAD)-dependent enzymes.
이러한 HDAC 중에서 HDAC6은 N-말단 및 중앙 영역에 각각 CD1 및 CD2 촉매 도메인을 포함하는 1215개의 아미노산 잔기로 구성되어 있다. C-말단에는 유비퀴틴 프로테아솜과 어그레솜 경로 사이의 상호작용을 촉진하는 아연-핑거 유비퀴틴 결합 도메인을 가지고 있다. HDAC6는 히스톤의 탈아세틸화 외에도 α-튜불린, 코르탁틴, 타우, 퍼옥시레독신 및 열충격단백질(HSP90)과 같은 비히스톤 단백을 기질로 하여 탈아세틸화를 유도한다. Among these HDACs, HDAC6 consists of 1215 amino acid residues, including CD1 and CD2 catalytic domains in the N-terminal and central regions, respectively. The C-terminus contains a zinc-finger ubiquitin binding domain that promotes the interaction between the ubiquitin proteasome and aggresome pathways. In addition to deacetylation of histones, HDAC6 also induces deacetylation using non-histone proteins such as α-tubulin, cortactin, tau, peroxiredoxin, and heat shock protein (HSP90) as substrates.
다수의 보고에 따르면, HDAC6은 세포 이동, 자가포식(autophagy), 세포내이입(endocytosis), 단백질 수송, 세포자멸사(apoptosis) 및 분해와 같은 다양한 생리학적 과정과 관련되며, 이러한 중요한 생리학적 기능으로 인해 HDAC6은 암, 염증 및 면역 장애와 같은 다양한 인간 질병에 대한 효과적인 치료 표적이 되고 있다.According to numerous reports, HDAC6 is involved in various physiological processes such as cell migration, autophagy, endocytosis, protein transport, apoptosis, and degradation, and has these important physiological functions. Because of this, HDAC6 has become an effective therapeutic target for various human diseases such as cancer, inflammation, and immune disorders.
현재까지 다양한 종류의 HDAC 저해제가 연구 개발되었으며, 5종의 FDA 승인된 HDAC 저해 항암약물이 사용 중이다. 하지만 이들 약물은 비선택적 HDAC 저해제로서 이로 인한 부작용이 경감된 특성 아이소폼을 타겟하는 선택적 저해제 개발이 요구되고 있다. HDAC 아형 간의 유사성이 커서 아형선택적 저해제의 발굴이 쉽지 않은 과제이나 보다 선택적이고 효과적인 HDAC6 저해제 개발에 대한 요구도는 높은 실정이다.To date, various types of HDAC inhibitors have been researched and developed, and five types of FDA-approved HDAC inhibitory anticancer drugs are in use. However, these drugs are non-selective HDAC inhibitors, and there is a need to develop selective inhibitors targeting characteristic isoforms with reduced side effects. The similarity between HDAC subtypes is large, so discovering subtype-selective inhibitors is not an easy task, but there is a high demand for the development of more selective and effective HDAC6 inhibitors.
본 발명의 목적은 신규 HDAC6 저해제를 제공하는 데에 있다.The purpose of the present invention is to provide a novel HDAC6 inhibitor.
본 발명의 다른 목적은 상기 신규 HDAC6 저해제를 이용한 HDAC6 저해방법을 제공하는 데에 있다.Another object of the present invention is to provide a method of inhibiting HDAC6 using the novel HDAC6 inhibitor.
본 발명의 또 다른 목적은 신규 HDAC6 저해제 발굴을 통한 HDAC6 관련 질환 치료제를 제공하는 데에 있다.Another purpose of the present invention is to provide a treatment for HDAC6-related diseases through discovery of new HDAC6 inhibitors.
본 발명의 다른 목적은 신규 HDAC6 저해제를 HDAC6 관련 질환 치료가 필요한 대상체에 투여하는 단계를 포함하는 HDAC6 관련 질환 치료방법을 제공하는 데에 있다.Another object of the present invention is to provide a method of treating HDAC6-related diseases, including the step of administering a novel HDAC6 inhibitor to a subject in need of treatment for HDAC6-related diseases.
본 발명은 하기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염에서 선택된 화합물을 제공한다:The present invention provides a compound selected from the compounds represented by the following formula (1) or pharmaceutically acceptable salts thereof:
[화학식 1][Formula 1]
Figure PCTKR2023003562-appb-img-000001
Figure PCTKR2023003562-appb-img-000001
상기 화학식 1에서, In Formula 1,
X는 수소, 불소, 염소 또는 브롬에서 선택되고,X is selected from hydrogen, fluorine, chlorine or bromine,
A는 치환되거나 치환되지 않은 페닐, 나프틸 또는 헤테로고리 화합물에서 선택되고,A is selected from substituted or unsubstituted phenyl, naphthyl or heterocyclic compounds,
상기 치환은 (C1~C10)알킬, (C1~C10)알콕시, 할로, 다이플루오로메틸, 트리플루오로메틸, 하이드록시, 시아노, 나이트로, 페닐, 벤질옥시 또는 페녹시에서 선택된 하나 이상의 치환기로 치환되고, The substitution is one or more substituents selected from (C1~C10)alkyl, (C1~C10)alkoxy, halo, difluoromethyl, trifluoromethyl, hydroxy, cyano, nitro, phenyl, benzyloxy, or phenoxy. is replaced with,
상기 헤테로고리 화합물은 5환 또는 6환의 헤테로아릴 화합물이며,The heterocyclic compound is a 5- or 6-ring heteroaryl compound,
n은 1 내지 3의 정수임.n is an integer from 1 to 3.
또한, 본 발명은 상기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염에서 선택된 화합물을 포함하는 히스톤 탈아세틸화 효소6(Histone deacetylase 6; HDAC6) 관련 질환 치료 또는 예방용 약학조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for the treatment or prevention of diseases related to histone deacetylase 6 (HDAC6), comprising a compound selected from the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof. .
또한, 본 발명은 상기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염에서 선택된 화합물을 포함하는 히스톤 탈아세틸화 효소6(Histone deacetylase 6; HDAC6) 관련 질환 개선 또는 예방용 건강기능식품을 제공한다.In addition, the present invention provides a health functional food for improving or preventing diseases related to histone deacetylase 6 (HDAC6), comprising a compound selected from the compounds represented by Formula 1 or pharmaceutically acceptable salts thereof. do.
또한, 본 발명은 상기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염에서 선택된 화합물을 포함하는 히스톤 탈아세틸화 효소6(Histone deacetylase 6; HDAC6) 저해용 조성물을 제공한다.In addition, the present invention provides a composition for inhibiting histone deacetylase 6 (HDAC6) comprising a compound selected from the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
또한, 본 발명은 상기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염에서 선택된 화합물을 처리하는 단계를 포함하는 히스톤 탈아세틸화 효소6(Histone deacetylase 6; HDAC6) 저해방법을 제공한다.In addition, the present invention provides a method of inhibiting histone deacetylase 6 (HDAC6), which includes the step of treating a compound selected from the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
또한, 본 발명은 상기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염에서 선택된 화합물을 히스톤 탈아세틸화 효소6(Histone deacetylase 6; HDAC6) 관련 질환을 앓고 있는 대상체에 투여하는 단계를 포함하는 히스톤 탈아세틸화 효소6(Histone deacetylase 6; HDAC6) 관련 질환 치료방법을 제공한다.In addition, the present invention includes the step of administering a compound selected from the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof to a subject suffering from a disease related to histone deacetylase 6 (HDAC6). Provides a treatment method for diseases related to histone deacetylase 6 (HDAC6).
본 발명은 신규 헤테로고리 히스톤 탈아세틸화 효소 저해제에 관한 것으로, 특히 히스톤 탈아세틸화 효소(Histone deacetylase; HDAC) 중에서도 HDAC6에 대해 보다 선택적이고 효과적인 HDAC6 저해제를 제공함으로써 HDAC6 관련 질환, 예를 들어 암질환, 염증질환, 자가면역질환, 섬유화 질환 및 퇴행성질환과 같은 다양한 질환 치료제 개발이 가능하다.The present invention relates to a novel heterocyclic histone deacetylase inhibitor. In particular, it provides a more selective and effective HDAC6 inhibitor for HDAC6 among histone deacetylase (HDAC) enzymes, thereby treating HDAC6-related diseases, such as cancer. , it is possible to develop treatments for various diseases such as inflammatory diseases, autoimmune diseases, fibrotic diseases, and degenerative diseases.
이하, 본 발명을 보다 상세하게 설명한다.Hereinafter, the present invention will be described in more detail.
본 발명자는 보다 효과적인 HDAC6 저해제를 개발하기 위해 예의 노력한 결과, 인다졸 기반의 신규 HDAC6 저해제를 합성하였고, 우수한 HDAC6 저해 활성을 확인함으로써 본 발명을 완성하였다.As a result of diligent efforts to develop a more effective HDAC6 inhibitor, the present inventor synthesized a new indazole-based HDAC6 inhibitor and completed the present invention by confirming its excellent HDAC6 inhibitory activity.
이에, 본 발명은 하기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염에서 선택된 화합물을 제공한다:Accordingly, the present invention provides a compound selected from the compounds represented by the following formula (1) or pharmaceutically acceptable salts thereof:
[화학식 1][Formula 1]
Figure PCTKR2023003562-appb-img-000002
Figure PCTKR2023003562-appb-img-000002
상기 화학식 1에서, In Formula 1,
X는 수소, 불소, 염소 또는 브롬에서 선택되고,X is selected from hydrogen, fluorine, chlorine or bromine,
A는 치환되거나 치환되지 않은 페닐, 나프틸 또는 헤테로고리 화합물에서 선택되고,A is selected from substituted or unsubstituted phenyl, naphthyl or heterocyclic compounds,
상기 치환은 (C1~C10)알킬, (C1~C10)알콕시, 할로, 다이플루오로메틸, 트리플루오로메틸, 하이드록시, 시아노, 나이트로, 페닐, 벤질옥시 또는 페녹시에서 선택된 하나 이상의 치환기로 치환되고, The substitution is one or more substituents selected from (C1~C10)alkyl, (C1~C10)alkoxy, halo, difluoromethyl, trifluoromethyl, hydroxy, cyano, nitro, phenyl, benzyloxy, or phenoxy. is replaced with,
상기 헤테로고리 화합물은 5환 또는 6환의 헤테로아릴 화합물이며,The heterocyclic compound is a 5- or 6-ring heteroaryl compound,
n은 1 내지 3의 정수일 수 있다.n may be an integer from 1 to 3.
상기 헤테로고리 화합물은 티오펜, 퓨란, 피로졸, 피리딘, 피란, 옥사진, 티아진, 피리미딘 및 피페라진으로 이루어진 군에서 선택될 수 있지만, 이에 한정되는 것은 아니다.The heterocyclic compound may be selected from the group consisting of thiophene, furan, pyrazole, pyridine, pyran, oxazine, thiazine, pyrimidine, and piperazine, but is not limited thereto.
바람직하게는, 상기 화합물은 하기 화학식 1-1로 표시되는 화합물일 수 있다:Preferably, the compound may be a compound represented by the following formula 1-1:
[화학식 1-1][Formula 1-1]
Figure PCTKR2023003562-appb-img-000003
Figure PCTKR2023003562-appb-img-000003
상기 화학식 1-1에서,In Formula 1-1,
X는 수소 또는 불소이고,X is hydrogen or fluorine,
A는 페닐, 나프틸 또는 피리미딜에서 선택되고,A is selected from phenyl, naphthyl or pyrimidyl,
R1 및 R2는 각각 동일하거나 다를 수 있고, 수소, (C1~C4)알킬, (C1~C4)알콕시, 할로, 다이플루오로메틸, 트리플루오로메틸, 페닐, 벤질옥시 또는 페녹시에서 선택되며, R 1 and R 2 may each be the same or different and are selected from hydrogen, (C1~C4)alkyl, (C1~C4)alkoxy, halo, difluoromethyl, trifluoromethyl, phenyl, benzyloxy, or phenoxy. And
n은 1 내지 3의 정수일 수 있다.n may be an integer from 1 to 3.
보다 바람직하게는, 상기 화합물은 i) A는 페닐, 나프틸 또는 피리미딜에서 선택되고, R1은 수소, (C1~C4)알킬, (C1~C4)알콕시, 할로, 다이플루오로메틸, 트리플루오로메틸, 페닐, 벤질옥시 또는 페녹시에서 선택되며, R2는 수소, (C1~C4)알콕시 또는 할로에서 선택되며, n은 1 내지 2의 정수일 수 있다.More preferably, the compound is i) A is selected from phenyl, naphthyl or pyrimidyl, and R 1 is hydrogen, (C1~C4)alkyl, (C1~C4)alkoxy, halo, difluoromethyl, tri It is selected from fluoromethyl, phenyl, benzyloxy or phenoxy, R 2 is selected from hydrogen, (C1~C4)alkoxy or halo, and n may be an integer of 1 to 2.
일 실시예로는, 상기 화합물은 2-벤질-2H-인다졸-6-카르복실산 하이드록시아마이드(2-Benzyl-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 50); 2-(4-메톡시벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(4-Methoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 51); 2-(4-메틸벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(4-Methylbenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 52); 2-(4-플루오로벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(4-Fluorobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 53); 2-(4-클로로벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(4-Chlorobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 54); 2-(4-브로모벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(4-Bromobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 55); 2-(3-트리플루오로메톡시벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(3-Trifluoromethoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 56); 2-(4-트리플루오로메톡시벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(4-Trifluoromethoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 57); 2-나프탈렌-2-일메틸-2H-인다졸-6-카르복실산 하이드록시아마이드(2-Naphthalen-2-ylmethyl-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 58); 2-페네틸-2H-인다졸-6-카르복실산 하이드록시아마이드(2-Phenethyl-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 59); 2-(2-4-메톡시페닐에틸)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(2-4-Methoxyphenylethyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 60); 2-(3,5-다이플로오로벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(3,5-Difluorobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 61); 2-(4-다이플루오로메톡시벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(4-Difluoromethoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 62); 2-바이페닐-4-일메틸-2H-인다졸-6-카르복실산 하이드록시아마이드(2-Biphenyl-4-ylmethyl-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 63); 2-(4-아이소프로필벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(4-Isopropylbenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 64); 2-(2-(4-플루오로페닐)에틸)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(2-(4-Fluorophenyl)ethyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 65); 2-(3-플루오로벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(3-Fluorobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 66); 2-(3-클로로벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(3-Chlorobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 67); 2-(3-트리플루오로메틸벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(3-Trifluoromethylbenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 68); 2-(4-트리플루오로메틸벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(4-Trifluoromethylbenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 69); 2-(3-메톡시벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(3-Methoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 70); 2-(3-벤질옥시벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(3-Benzyloxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 71); 2-(3,5-다이메톡시벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(3,5-Dimethoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 72); 2-(3-페녹시벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(3-Phenoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 73); 2-피리딘-3-일메틸-2H-인다졸-6-카르복실산 하이드록시아마이드(2-Pyridin-3-ylmethyl-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 76); 2-벤질-5-플루오로-2H-인다졸-6-카르복실산 하이드록시아마이드(2-Benzyl-5-fluoro-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 88); 2-(3-클로로벤질)-5-플루오로-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(3-Chlorobenzyl)-5-fluoro-2H-indazole-6-carboxylic acid hydroxyamide; 화합물　89); 및 2-(3-메톡시벤질)-5-플루오로-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(3-Methoxybenzyl)-5-fluoro-2H-indazole-6-carboxylic acid hydroxyamide; 화합물　90);로 이루어진 군에서 선택될 수 있다.In one embodiment, the compound is 2-Benzyl-2 H -indazole-6-carboxylic acid hydroxyamide (Compound 50 ); 2-(4 - Methoxybenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 51); 2-(4 - Methylbenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 52); 2-(4 - Fluorobenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 53); 2-(4 - Chlorobenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 54); 2-(4 - Bromobenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 55); 2-(3 - Trifluoromethoxybenzyl) -2H- indazole-6-carboxylic acid hydroxyamide (Compound 56); 2-(4 - Trifluoromethoxybenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 57); 2-Naphthalen-2-ylmethyl- 2H -indazole-6-carboxylic acid hydroxyamide (Compound 58 ) ; 2 - Phenethyl-2 H- indazole-6-carboxylic acid hydroxyamide (Compound 59); 2-(2-4 - Methoxyphenylethyl) -2H -indazole-6-carboxylic acid hydroxyamide; compound 60); 2-(3,5-difluorobenzyl)-2 H -indazole-6-carboxylic acid hydroxyamide (2-(3,5-Difluorobenzyl)-2 H -indazole-6-carboxylic acid hydroxyamide; compound 61); 2-(4 - difluoromethoxybenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 62); 2-Biphenyl-4-ylmethyl- 2H -indazole-6-carboxylic acid hydroxyamide (Compound 63 ) ; 2-(4 - Isopropylbenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 64); 2-(2-(4-Fluorophenyl)ethyl) -2H -indazole-6-carboxylic acid hydroxyamide (2-(2-(4-Fluorophenyl)ethyl)-2H - indazole-6- carboxylic acid hydroxyamide; compound 65); 2-(3 - Fluorobenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 66); 2-(3 - Chlorobenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 67); 2-(3 - Trifluoromethylbenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 68); 2-(4 - Trifluoromethylbenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 69); 2-(3 - Methoxybenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 70); 2-(3 - Benzyloxybenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 71); 2-(3,5-dimethoxybenzyl)-2 H -indazole-6-carboxylic acid hydroxyamide (2-(3,5-Dimethoxybenzyl)-2 H -indazole-6-carboxylic acid hydroxyamide; compound 72); 2-(3 - Phenoxybenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 73); 2-Pyridin-3-ylmethyl - 2H -indazole-6-carboxylic acid hydroxyamide (Compound 76); 2-Benzyl-5-fluoro- 2H -indazole-6-carboxylic acid hydroxyamide (Compound 88 ); 2- ( 3-Chlorobenzyl)-5-fluoro- 2H -indazole-6-carboxylic acid hydroxyamide; compound 89); and 2-(3-methoxybenzyl)-5-fluoro- 2H -indazole-6-carboxylic acid hydroxyamide (2-(3-Methoxybenzyl)-5-fluoro- 2H- indazole-6- It may be selected from the group consisting of carboxylic acid hydroxyamide; Compound 90);
본 발명에 따른 화합물은 히스톤 탈아세틸화 효소6(Histone deacetylase 6; HDAC6)을 보다 선택적으로 억제할 수 있다.The compound according to the present invention can more selectively inhibit histone deacetylase 6 (HDAC6).
상기 ‘약제학적으로 허용가능한 염’은 약제학적으로 허용가능한 염기성 염 또는 산성 염 중 어느 하나의 형태로 사용할 수 있다. 염기성 염으로는 유기염기염, 무기염기염 중 어느 하나의 형태로 사용할 수 있으며, 예를 들어 나트륨염, 칼륨염, 칼슘염, 리튬염, 마그네슘염, 세슘염 및 아미늄(aminium)염, 암모늄염, 트리에틸아미늄염, 피리디늄염 등을 사용할 수 있으나, 이에 한정되는 것은 아니다.The ‘pharmaceutically acceptable salt’ may be used in the form of either a pharmaceutically acceptable basic salt or an acidic salt. Basic salts can be used in the form of either organic base salts or inorganic base salts, such as sodium salts, potassium salts, calcium salts, lithium salts, magnesium salts, cesium salts, aminium salts, and ammonium salts. , triethylaminium salt, pyridinium salt, etc. can be used, but are not limited thereto.
또한, 산성 염은 유리산(free acid)에 의해 형성된 산부가염이 유용하다. 유리산으로는 무기산과 유기산을 사용할 수 있으며, 무기산으로는 염산, 브롬산, 황산, 아황산, 인산 등을 사용할 수 있고, 유기산으로는 구연산, 초산, 말레산, 퓨마르산, 글루코산, 메탄설폰산, 벤젠설폰산, 캠퍼설폰산, 옥살산, 말론산, 글루타릭산, 아세트산, 글리콘산, 석신산, 타타르산, 4-톨루엔설폰산, 갈락투론산, 엠본산, 글루탐산, 시트르산, 아스파르탄산 등을 사용할 수 있다. 바람직하게는 무기산으로는 염산, 유기산으로는 메탄설폰산을 사용할 수 있다.Additionally, an acid addition salt formed by a free acid is useful as the acid salt. Inorganic acids and organic acids can be used as free acids. Hydrochloric acid, hydrobromic acid, sulfuric acid, sulfurous acid, and phosphoric acid can be used as inorganic acids, and citric acid, acetic acid, maleic acid, fumaric acid, gluconic acid, and methanesulfonic acid can be used as organic acids. , benzenesulfonic acid, camphorsulfonic acid, oxalic acid, malonic acid, glutaric acid, acetic acid, glyconic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, citric acid, aspartic acid. etc. can be used. Preferably, hydrochloric acid can be used as the inorganic acid, and methanesulfonic acid can be used as the organic acid.
또한, 본 발명에 따른 화합물은 약제학적으로 허용되는 염뿐만 아니라, 통상의 방법에 의해 제조될 수 있는 모든 염, 수화물 및 용매화물을 모두 포함할 수 있다.In addition, the compound according to the present invention may include not only pharmaceutically acceptable salts, but also all salts, hydrates, and solvates that can be prepared by conventional methods.
본 발명에 따른 부가염은 통상의 방법으로 제조할 수 있으며, 예를 들면 상기 화합물을 수혼화성 유기용매, 예를 들면 아세톤, 메탄올, 에탄올, 또는 아세토니트릴 등에 녹이고 과량의 유기염기를 가하거나 무기염기의 염기 수용액을 가한 후 침전시키거나 결정화시켜서 제조할 수 있다. 또는 이 혼합물에서 용매나 과량의 염기를 증발시킨 후 건조시켜서 부가염을 얻거나 또는 석출된 염을 흡인 여과시켜 제조할 수 있다.The addition salt according to the present invention can be prepared by conventional methods. For example, the compound is dissolved in a water-miscible organic solvent, such as acetone, methanol, ethanol, or acetonitrile, and an excess amount of organic base is added or an inorganic base is added. It can be prepared by adding an aqueous solution of a base and then precipitating or crystallizing it. Alternatively, an addition salt can be obtained by evaporating the solvent or excess base from this mixture and drying it, or it can be prepared by suction filtration of the precipitated salt.
또한, 본 발명은 상기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염에서 선택된 화합물을 포함하는 히스톤 탈아세틸화 효소6(Histone deacetylase 6; HDAC6) 관련 질환 치료 또는 예방용 약학조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for the treatment or prevention of diseases related to histone deacetylase 6 (HDAC6), comprising a compound selected from the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof. .
또한, 본 발명은 상기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염에서 선택된 화합물을 히스톤 탈아세틸화 효소6(Histone deacetylase 6; HDAC6) 관련 질환을 앓고 있는 대상체에 투여하는 단계를 포함하는 히스톤 탈아세틸화 효소6(Histone deacetylase 6; HDAC6) 관련 질환 치료방법을 제공한다.In addition, the present invention includes the step of administering a compound selected from the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof to a subject suffering from a disease related to histone deacetylase 6 (HDAC6). Provides a treatment method for diseases related to histone deacetylase 6 (HDAC6).
상기 히스톤 탈아세틸화 효소6(Histone deacetylase 6; HDAC6) 관련 질환은 암질환, 염증질환, 자가면역질환, 섬유화 질환 및 퇴행성질환으로 이루어진 군에서 선택될 수 있다.The histone deacetylase 6 (HDAC6)-related disease may be selected from the group consisting of cancer disease, inflammatory disease, autoimmune disease, fibrotic disease, and degenerative disease.
상기 암질환은 결장암, 폐암, 신장암, 방광암, 간암, 흉선암, 난소암, 자궁경부암, 유방암, 대장암, 위암, 췌장암, 결장암, 복막 전이암, 피부암, 방광암, 전립선암, 골육종, 섬유성 종양, 뇌종양, 급성 림프구성 백혈병, 급성 골수성 백혈병, 림프종 및 신경모세포종으로 이루어지는 군으로부터 선택될 수 있지만, 이에 한정되는 것은 아니다. The above cancer diseases include colon cancer, lung cancer, kidney cancer, bladder cancer, liver cancer, thymus cancer, ovarian cancer, cervical cancer, breast cancer, colon cancer, stomach cancer, pancreas cancer, colon cancer, peritoneal metastasis, skin cancer, bladder cancer, prostate cancer, osteosarcoma, and fibrous cancer. It may be selected from the group consisting of tumor, brain tumor, acute lymphoblastic leukemia, acute myeloid leukemia, lymphoma, and neuroblastoma, but is not limited thereto.
상기 염증질환 또는 자가면역질환은 골관절염, 류마티스 관절염(Rheumatoid Arthritis), 피부염, 알레르기, 아토피, 천식, 건선, 결막염, 비염, 중이염, 인후염, 편도염, 폐렴, 위궤양, 위염, 크론병, 염증성 장질환(inflammatory bowel disease), 루푸스, 간염, 방광염, 간질성방광염, 신장염, 쇼그렌 증후군(sjogren's syndrome), 다발성 경화증, 하시모토 갑상선(Hashimoto thyroiditis), 다발성근염(polymyositis), 경피증(scleroderma), 아디슨병(Addison disease), 백반증(vitiligo), 악성빈혈(pernicious anemia), 낭섬유증(Cystic Fibrosis), 이식편대숙주질환(graft-versus-host disease), 이식거부질환, 자가면역성 당뇨(Autoimmune Diabetes), 당뇨 망막증(Diabetic retinopathy), 허혈-재관류 손상(Ischemia-reperfusion injury), 혈관성형술후 재협착(Post-angioplasty restenosis), 만성 폐색성 심장 질환(Chronic obstructive pulmonary disease; COPD), 그레이브병(Graves disease) 및 급성 및 만성 염증 질환으로 이루어진 군에서 선택될 수 있지만, 이에 한정되는 것은 아니다.The inflammatory or autoimmune diseases include osteoarthritis, rheumatoid arthritis, dermatitis, allergy, atopy, asthma, psoriasis, conjunctivitis, rhinitis, otitis media, pharyngitis, tonsillitis, pneumonia, gastric ulcer, gastritis, Crohn's disease, and inflammatory bowel disease ( inflammatory bowel disease, lupus, hepatitis, cystitis, interstitial cystitis, nephritis, Sjogren's syndrome, multiple sclerosis, Hashimoto thyroiditis, polymyositis, scleroderma, Addison disease ), vitiligo, pernicious anemia, cystic fibrosis, graft-versus-host disease, transplant rejection disease, autoimmune diabetes, diabetic retinopathy retinopathy, ischemia-reperfusion injury, Post-angioplasty restenosis, Chronic obstructive pulmonary disease (COPD), Graves disease, and acute and chronic It may be selected from the group consisting of inflammatory diseases, but is not limited thereto.
상기 섬유화 질환은 폐섬유증, 신섬유증, 심장섬유증, 간섬유증, 경피증, 골격근 섬유증 및 당뇨성 섬유증으로 이루어진 군에서 선택될 수 있지만, 이에 한정되는 것은 아니다.The fibrotic disease may be selected from the group consisting of pulmonary fibrosis, renal fibrosis, cardiac fibrosis, liver fibrosis, scleroderma, skeletal muscle fibrosis, and diabetic fibrosis, but is not limited thereto.
또한, 상기 간섬유증은 비알콜성 지방간염(NASH) 또는 비알콜성 지방 간 질환(NAFLD)을 포함할 수 있지만, 이에 한정되는 것은 아니다.Additionally, the liver fibrosis may include, but is not limited to, nonalcoholic steatohepatitis (NASH) or nonalcoholic fatty liver disease (NAFLD).
상기 퇴행성질환은 뇌졸중, 중풍, 기억력 상실, 기억력 손상, 치매, 건망증, 파킨슨병, 알츠하이머병, 피크(Pick)병, 크로이츠펠트-야콥 (Creutzfeld-Kacob)병, 헌팅턴병 및 루게릭병으로 이루어진 군에서 선택된 퇴행성 신경질환일 수 있지만, 이에 한정되는 것은 아니다.The degenerative disease is selected from the group consisting of stroke, paralysis, memory loss, memory impairment, dementia, amnesia, Parkinson's disease, Alzheimer's disease, Pick's disease, Creutzfeld-Jakob disease, Huntington's disease, and Lou Gehrig's disease. It may be a degenerative neurological disease, but it is not limited to this.
상기 약학조성물은 통상적인 방법에 따라 겔제, 유제, 주사제, 산제, 과립제, 에어로솔제, 페이스트제, 경피흡수제 및 패치제로 이루어진 군에서 선택된 하나 이상의 제형으로 제공될 수 있으나, 이에 제한되는 것은 아니다.The pharmaceutical composition may be provided in one or more formulations selected from the group consisting of gels, emulsions, injections, powders, granules, aerosols, pastes, transdermal absorbents, and patches according to conventional methods, but is not limited thereto.
본 발명의 다른 구체예에서, 상기 약학조성물은 약학조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제, 붕해제, 감미제, 피복제, 팽창제, 윤활제, 활택제, 향미제, 항산화제, 완충액, 정균제, 희석제, 분산제, 계면활성제, 결합제 및 윤활제로 이루어진 군에서 선택되는 하나 이상의 첨가제를 추가로 포함할 수 있다.In another embodiment of the present invention, the pharmaceutical composition includes suitable carriers, excipients, disintegrants, sweeteners, coating agents, swelling agents, lubricants, lubricants, flavoring agents, antioxidants, buffers, and bacteriostatic agents commonly used in the preparation of pharmaceutical compositions. , it may further include one or more additives selected from the group consisting of diluents, dispersants, surfactants, binders, and lubricants.
구체적으로 담체, 부형제 및 희석제는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 사용할 수 있으며, 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 조성물에 적어도 하나 이상의 부형제, 예를 들면, 전분, 칼슘카보네이트, 수크로스 또는 락토오스, 젤라틴 등을 섞어 조제할 수 있다. 또한 단순한 부형제 이외에 마그네슘 스티레이트, 탈크 같은 윤활제들도 사용할 수 있다. 경구를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 있으며 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제 등이 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜, 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기재로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.Specifically, carriers, excipients, and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, and microcrystalline. Cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil can be used. Solid preparations for oral administration include tablets, pills, powders, granules, and capsules. agents, etc., and such solid preparations can be prepared by mixing the composition with at least one or more excipients, such as starch, calcium carbonate, sucrose or lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium styrate and talc can also be used. Liquid preparations for oral use include suspensions, oral solutions, emulsions, and syrups. In addition to the commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. Preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, etc. Non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate. As a base for suppositories, witepsol, macrogol, tween 61, cacao, laurin, glycerogeratin, etc. can be used.
상기 약학조성물은 정맥내, 동맥내, 복강내, 근육내, 동맥내, 복강내, 흉골내, 경피, 비측내, 흡입, 국소, 직장, 경구, 안구내 또는 피내 경로를 통해 통상적인 방식으로 대상체로 투여할 수 있다.The pharmaceutical composition may be administered to the subject in a conventional manner via intravenous, intraarterial, intraperitoneal, intramuscular, intraarterial, intraperitoneal, intrasternal, transdermal, intranasal, inhalation, topical, rectal, oral, intraocular or intradermal routes. It can be administered.
상기 화합물의 바람직한 투여량은 대상체의 상태 및 체중, 질환의 종류 및 정도, 약물 형태, 투여경로 및 기간에 따라 달라질 수 있으며 당업자에 의해 적절하게 선택될 수 있다. 본 발명의 일실시예에 따르면 이에 제한되는 것은 아니지만 1일 투여량이 0.01 내지 200 mg/kg, 구체적으로는 0.1 내지 200 mg/kg, 보다 구체적으로는 0.1 내지 100 mg/kg 일 수 있다. 투여는 하루에 한 번 투여할 수도 있고 수회로 나누어 투여할 수도 있으며, 이에 의해 본 발명의 범위가 제한되는 것은 아니다.The preferred dosage of the compound may vary depending on the subject's condition and weight, type and degree of disease, drug form, administration route and period, and may be appropriately selected by a person skilled in the art. According to one embodiment of the present invention, but is not limited thereto, the daily dosage may be 0.01 to 200 mg/kg, specifically 0.1 to 200 mg/kg, and more specifically 0.1 to 100 mg/kg. Administration may be administered once a day or may be divided into several administrations, and the scope of the present invention is not limited thereby.
본 발명에 있어서, 상기 '대상체'는 인간을 포함하는 포유동물일 수 있으나, 이들 예에 한정되는 것은 아니다.In the present invention, the 'subject' may be a mammal, including humans, but is not limited to these examples.
또한, 본 발명은 상기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염에서 선택된 화합물을 포함하는 히스톤 탈아세틸화 효소6(Histone deacetylase 6; HDAC6) 관련 질환 개선 또는 예방용 건강기능식품을 제공한다.In addition, the present invention provides a health functional food for improving or preventing diseases related to histone deacetylase 6 (HDAC6), comprising a compound selected from the compounds represented by Formula 1 or pharmaceutically acceptable salts thereof. do.
상기 "건강기능식품"이라 함은 건강기능 식품에 관한 법률에 따른 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 의미하며, "기능성"이라 함은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 얻을 목적으로 섭취하는 것을 의미한다.The term "health functional food" refers to food manufactured and processed using raw materials or ingredients with functionality useful to the human body in accordance with the Health Functional Food Act, and "functional" refers to food that is related to the structure and function of the human body. It means ingestion for the purpose of controlling nutrients or obtaining useful health effects such as physiological effects.
상기 건강기능식품은 통상의 식품 첨가물을 포함할 수 있으며, 상기 "식품 첨가물"로서의 적합 여부는 다른 규정이 없는 한, 식품의약품안전처에 승인된 식품 첨가물 공전의 총칙 및 일반시험법 등에 따라 해당 품목에 관한 규격 및 기준에 의하여 판정한다.The above-mentioned health functional food may contain ordinary food additives, and the suitability of the above-mentioned “food additive” is determined in accordance with the general provisions of the Food Additive Code and General Test Methods approved by the Ministry of Food and Drug Safety, unless otherwise specified. It is determined in accordance with the relevant standards and standards.
상기 "식품 첨가물 공전"에 수재된 품목으로는 예를 들어, 케톤류, 글리신, 구연산칼륨, 니코틴산, 계피산 등의 화학적 합성물, 감색소, 감초추출물, 결정셀룰로오스, 고량색소, 구아검 등의 천연첨가물, L-글루타민산나트륨 제제, 면류첨가알칼리제, 보존료제제, 타르색소제제 등의 혼합제제류들을 들 수 있다.Items listed in the "Food Additives Code" include, for example, chemical compounds such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid; natural additives such as subchromic pigment, licorice extract, crystalline cellulose, high-liquid pigment, and guar gum; Examples include mixed preparations such as sodium L-glutamate preparations, noodle additive alkaline preparations, preservative preparations, and tar coloring preparations.
상기 건강기능식품에 함유된 유효성분의 유효용량은 상기 치료제의 유효용량에 준해서 사용할 수 있으나, 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 범위 이하일 수 있으며, 유효성분은 안전성 면에서 아무런 문제가 없기 때문에 상기 범위 이상의 양으로도 사용될 수 있음은 확실하다.The effective dose of the active ingredient contained in the health functional food may be used in accordance with the effective dose of the therapeutic agent, but in the case of long-term intake for the purpose of health and hygiene or health control, it may be below the above range. , It is certain that the active ingredient can be used in amounts exceeding the above range because there is no problem in terms of safety.
상기 건강기능식품의 종류에는 특별한 제한이 없고, 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제등을 들 수 있다.There are no particular restrictions on the types of health functional foods, and examples include meat, sausages, bread, chocolate, candies, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, and tea. , drinks, alcoholic beverages, and vitamin complexes.
또한, 본 발명은 상기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염에서 선택된 화합물을 포함하는 히스톤 탈아세틸화 효소6(Histone deacetylase 6; HDAC6) 저해용 조성물을 제공한다.In addition, the present invention provides a composition for inhibiting histone deacetylase 6 (HDAC6) comprising a compound selected from the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
또한, 본 발명은 상기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염에서 선택된 화합물을 처리하는 단계를 포함하는 히스톤 탈아세틸화 효소6(Histone deacetylase 6; HDAC6) 저해방법을 제공한다.In addition, the present invention provides a method of inhibiting histone deacetylase 6 (HDAC6), which includes the step of treating a compound selected from the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
상기 화합물에 대한 설명은 앞서 기재한 설명과 동일하여 반복적인 기재를 생략한다.The description of the compound is the same as the previously described description, so repetitive description is omitted.
상기 조성물은 약학조성물, 건강기능식품, 시약조성물 등으로 활용될 수 있다.The composition can be used as a pharmaceutical composition, health functional food, reagent composition, etc.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 본 발명이 속하는 기술분야에서 통상의 지식을 가진 자에 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention in more detail, and it is understood by those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. It will be self-evident.
<실시예> HDAC6 저해제로서 인다졸 유도체 합성<Example> Synthesis of indazole derivatives as HDAC6 inhibitors
HDAC6 저해제로서 인다졸 유도체는 하기 반응식 1, 반응식 2 또는 반응식 3에 따른 일반적 공정에 의해 합성되었다. 구체적인 합성 과정은 이후 각 화합물별로 상세하게 설명한다.Indazole derivatives as HDAC6 inhibitors were synthesized by the general process according to Scheme 1, Scheme 2, or Scheme 3 below. The specific synthesis process will be described in detail for each compound later.
[반응식 1][Scheme 1]
Figure PCTKR2023003562-appb-img-000004
Figure PCTKR2023003562-appb-img-000004
(a) 알킬 브로마이드/클로라이드, Cs2CO3, DMF, 100℃, 4-8 시간; (a) Alkyl bromide/chloride, Cs 2 CO 3 , DMF, 100° C., 4-8 hours;
(b) 2N NaOH, MeOH, 실온(rt), 6-12 시간; (b) 2N NaOH, MeOH, room temperature (rt), 6-12 hours;
(c) NH2OH, BOP, DIPEA, DMSO, 실온(rt), 6-8 시간. (c) NH 2 OH, BOP, DIPEA, DMSO, room temperature (rt), 6-8 hours.
[반응식 2][Scheme 2]
Figure PCTKR2023003562-appb-img-000005
Figure PCTKR2023003562-appb-img-000005
(a) 알킬 브로마이드/클로라이드, Cs2CO3, DMF, 100℃, 4-8 시간; (a) Alkyl bromide/chloride, Cs 2 CO 3 , DMF, 100° C., 4-8 hours;
(b) 2N NaOH, MeOH, 실온(rt), 6-12 시간; (b) 2N NaOH, MeOH, room temperature (rt), 6-12 hours;
(c) NH2OH, BOP, DIPEA, DMSO, 실온(rt), 6-8 시간. (c) NH 2 OH, BOP, DIPEA, DMSO, room temperature (rt), 6-8 hours.
[반응식 3][Scheme 3]
Figure PCTKR2023003562-appb-img-000006
Figure PCTKR2023003562-appb-img-000006
(a) H2SO4, HNO3, 0℃, 3 시간;(a) H 2 SO 4 , HNO 3 , 0°C, 3 hours;
(b) H2SO4, MeOH, 65℃, 20 시간;(b) H 2 SO 4 , MeOH, 65° C., 20 hours;
(c) Pd/C, H2, EtOAc, 실온(rt), 2 시간;(c) Pd/C, H 2 , EtOAc, room temperature (rt), 2 hours;
(d) KOAc, AcOH, isoamyl nitrate, CHCl3, 실온(rt), 3 시간;(d) KOAc, AcOH, isoamyl nitrate, CHCl 3 , room temperature (rt), 3 hours;
(e) 알킬 브로마이드/클로라이드, Cs2CO3, DMF, 실온(rt), 2 시간;(e) Alkyl bromide/chloride, Cs 2 CO 3 , DMF, room temperature (rt), 2 hours;
(f) 2N NaOH, MeOH, THF, 실온(rt), 2 시간;(f) 2N NaOH, MeOH, THF, room temperature (rt), 2 hours;
(g) NH2OH, BOP, DIPEA, DMSO, 실온(rt), 6-8 시간. (g) NH 2 OH, BOP, DIPEA, DMSO, room temperature (rt), 6-8 hours.
1. One. N2N2 -치환된 2-substituted 2 HH -인다졸-6-카르복실산 메틸 에스테르 화합물 합성(화합물 2- 화합물 25, 화합물 74)-Indazole-6-carboxylic acid methyl ester compound synthesis (Compound 2- Compound 25, Compound 74)
DMF(15ml)에서 인다졸(1; 5.02 mmol), 알킬 브로마이드/클로라이드(5.52 mmol) 및 Cs2CO3(5.52mmol)의 혼합물을 100℃에서 4-8시간 동안 가열하여 반응시켰다. 반응 완료 후 반응 혼합물을 물에 넣고 에틸아세테이트로 조산물(crude product)을 추출하였다. 용출물로 헥산:에틸아세테이트(80:20)를 이용한 컬럼 크로마토그래피로 N2 치환된 인다졸 유도체(2-25, 74)를 각각 분리하였다.A mixture of indazole (1; 5.02 mmol), alkyl bromide/chloride (5.52 mmol) and Cs 2 CO 3 (5.52 mmol) in DMF (15 ml) was reacted by heating at 100°C for 4-8 hours. After completion of the reaction, the reaction mixture was added to water and the crude product was extracted with ethyl acetate. N2- substituted indazole derivatives (2-25, 74) were separated by column chromatography using hexane:ethyl acetate (80:20) as an eluent.
1) 2-벤질-2H-인다졸-6-카르복실산 메틸 에스테르[2-Benzyl-2H-indazole-6-carboxylic acid methyl ester; 화합물 2]1) 2-Benzyl-2 H -indazole-6-carboxylic acid methyl ester [2-Benzyl-2 H -indazole-6-carboxylic acid methyl ester; Compound 2]
흰색 고체; 수율 45%, 1H NMR (500 MHz, DMSO-d 6) δ 8.62 (s, 1H), 8.30 (s, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.42 - 7.29 (m, 5H), 5.72 (s, 2H), 3.88 (s, 3H).white solid; Yield 45%, 1H NMR (500 MHz, DMSO- d 6 ) δ 8.62 (s, 1H), 8.30 (s, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.57 (d, J = 8.7) Hz, 1H), 7.42 - 7.29 (m, 5H), 5.72 (s, 2H), 3.88 (s, 3H).
2) 2-(4-메톡시벤질)-2H-인다졸-5-카르복실산 메틸 에스테르[2-(4-Methoxybenzyl)-2H-indazole-5-carboxylic acid methyl ester; 화합물 3]2) 2-(4-Methoxybenzyl)-2 H -indazole-5-carboxylic acid methyl ester [2-(4-Methoxybenzyl)-2 H -indazole-5-carboxylic acid methyl ester; Compound 3]
흰색 고체; 수율 42%, 1H NMR (500 MHz, DMSO) δ 8.56 (s, 1H), 8.29 (s, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.35 (d, J = 8.6 Hz, 2H), 6.93 (d, J = 8.6 Hz, 2H), 5.63 (s, 2H), 3.88 (s, 3H), 3.73 (s, 3H). white solid; Yield 42%, 1H NMR (500 MHz, DMSO) δ 8.56 (s, 1H), 8.29 (s, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H) ), 7.35 (d, J = 8.6 Hz, 2H), 6.93 (d, J = 8.6 Hz, 2H), 5.63 (s, 2H), 3.88 (s, 3H), 3.73 (s, 3H).
3) 2-(4-메틸벤질)-2H-인다졸-6-카르복실산 메틸 에스테르[2-(4-Methylbenzyl)-2H-indazole-6-carboxylic acid methyl ester; 화합물 4]3) 2-(4-Methylbenzyl)-2 H -indazole-6-carboxylic acid methyl ester [2-(4-Methylbenzyl)-2 H -indazole-6-carboxylic acid methyl ester; Compound 4]
흰색 고체; 수율 40%, 1H NMR (500 MHz, DMSO-d 6) δ 8.58 (s, 1H), 8.29 (s, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.27 (d, J = 7.6 Hz, 2H), 7.17 (d, J = 7.6 Hz, 2H), 5.66 (s, 2H), 3.88 (s, 3H), 2.28 (s, 3H).white solid; Yield 40%, 1H NMR (500 MHz, DMSO- d 6 ) δ 8.58 (s, 1H), 8.29 (s, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.27 (d, J = 7.6 Hz, 2H), 7.17 (d, J = 7.6 Hz, 2H), 5.66 (s, 2H), 3.88 (s, 3H), 2.28 (s, 3H).
4) 2-(4-플루오로벤질)-2H-인다졸-6-카르복실산 메틸 에스테르[2-(4-Fluorobenzyl)-2H-indazole-6-carboxylic acid methyl ester; 화합물 5]4) 2-(4-Fluorobenzyl)-2 H -indazole-6-carboxylic acid methyl ester [2-(4-Fluorobenzyl)-2 H -indazole-6-carboxylic acid methyl ester; Compound 5]
흰색 고체; 수율 38%, 1H NMR (500 MHz, DMSO-d 6) δ 8.62 (s, 1H), 8.29 (s, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.49 - 7.40 (m, 2H), 7.23 - 7.17 (m, 2H), 5.71 (s, 2H), 3.88 (s, 3H).white solid; Yield 38%, 1H NMR (500 MHz, DMSO- d 6 ) δ 8.62 (s, 1H), 8.29 (s, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.57 (d, J = 8.7) Hz, 1H), 7.49 - 7.40 (m, 2H), 7.23 - 7.17 (m, 2H), 5.71 (s, 2H), 3.88 (s, 3H).
5) 2-(4-클로로벤질)-2H-인다졸-6-카르복실산 메틸 에스테르[2-(4-Chlorobenzyl)-2H-indazole-6-carboxylic acid methyl ester; 화합물 6]5) 2-(4-Chlorobenzyl)-2 H -indazole-6-carboxylic acid methyl ester [2-(4-Chlorobenzyl)-2 H -indazole-6-carboxylic acid methyl ester; Compound 6]
흰색 고체; 수율 41%, 1H NMR (500 MHz, DMSO-d 6) δ 8.63 (s, 1H), 8.29 (s, 1H), 7.84 (d, J = 9.5 Hz, 1H), 7.58 (d, J = 9.5 Hz, 1H), 7.44 (d, J = 8.5 Hz, 2H), 7.38 (d, J = 8.5 Hz, 2H), 5.73 (s, 2H), 3.88 (s, 3H).white solid; Yield 41%, 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.63 (s, 1H), 8.29 (s, 1H), 7.84 (d, J = 9.5 Hz, 1H), 7.58 (d, J = 9.5) Hz, 1H), 7.44 (d, J = 8.5 Hz, 2H), 7.38 (d, J = 8.5 Hz, 2H), 5.73 (s, 2H), 3.88 (s, 3H).
6) 2-(4-브로모벤질)-2H-인다졸-5-카르복실산 메틸 에스테르[2-(4-Bromobenzyl)-2H-indazole-5-carboxylic acid methyl ester; 화합물 7]6) 2-(4-Bromobenzyl)-2 H -indazole-5-carboxylic acid methyl ester [2-(4-Bromobenzyl)-2 H -indazole-5-carboxylic acid methyl ester; Compound 7]
흰색 고체; 수율 39%, 1H NMR (500 MHz, MeOD-d 4) δ 8.41 (s, 1H), 8.39 (s, 1H), 7.80 (d, J = 8.7 Hz, 1H), 7.69 (d, J = 8.7 Hz, 1H), 7.54 (d, J = 7.5 Hz, 2H), 7.27 (d, J = 7.5 Hz, 2H), 5.68 (s, 2H), 3.95 (s, 3H).white solid; Yield 39%, 1H NMR (500 MHz, MeOD- d 4 ) δ 8.41 (s, 1H), 8.39 (s, 1H), 7.80 (d, J = 8.7 Hz, 1H), 7.69 (d, J = 8.7 Hz) , 1H), 7.54 (d, J = 7.5 Hz, 2H), 7.27 (d, J = 7.5 Hz, 2H), 5.68 (s, 2H), 3.95 (s, 3H).
7) 2-(3-트리플루오로메톡시벤질)-2H-인다졸-5-카르복실산 메틸 에스테르[2-(3-Trifluoromethoxybenzyl)-2H-indazole-5-carboxylic acid methyl ester; 화합물 8]7) 2-(3-Trifluoromethoxybenzyl)-2 H -indazole-5-carboxylic acid methyl ester [2-(3-Trifluoromethoxybenzyl)-2 H -indazole-5-carboxylic acid methyl ester; Compound 8]
8) 2-(4-트리플루오로메톡시벤질)-2H-인다졸-5-카르복실산 메틸 에스테르[2-(4-Trifluoromethoxybenzyl)-2H-indazole-5-carboxylic acid methyl ester; 화합물 9]8) 2-(4-Trifluoromethoxybenzyl)-2 H -indazole-5-carboxylic acid methyl ester [2-(4-Trifluoromethoxybenzyl)-2 H -indazole-5-carboxylic acid methyl ester; Compound 9]
흰색 고체; 수율 40%, 1H NMR (500 MHz, DMSO-d 6) δ 8.65 (s, 1H), 8.31 (s, 1H), 7.86 - 7.27 (m, 6H), 5.77 (s, 2H), 3.88 (s, 3H).white solid; Yield 40%, 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.65 (s, 1H), 8.31 (s, 1H), 7.86 - 7.27 (m, 6H), 5.77 (s, 2H), 3.88 (s) , 3H).
9) 2-나프탈렌-2-일메틸-2H-인다졸-6-카르복실산 메틸 에스테르[2-Naphthalen-2-ylmethyl-2H-indazole-6-carboxylic acid methyl ester; 화합물 10]9) 2-Naphthalen-2-ylmethyl-2 H -indazole-6-carboxylic acid methyl ester [2-Naphthalen-2-ylmethyl-2 H -indazole-6-carboxylic acid methyl ester; Compound 10]
흰색 고체; 수율 45%, 1H NMR (500 MHz, DMSO-d 6) δ 8.68 (s, 1H), 8.30 (s, 1H), 7.93 - 7.89 (m, 4H), 7.85 (d, J = 8.8 Hz, 1H), 7.61 - 7.47 (m, 4H), 3.88 (s, 3H).white solid; Yield 45%, 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.68 (s, 1H), 8.30 (s, 1H), 7.93 - 7.89 (m, 4H), 7.85 (d, J = 8.8 Hz, 1H ), 7.61 - 7.47 (m, 4H), 3.88 (s, 3H).
10) 2-페네틸-2H-인다졸-5-카르복실산 메틸 에스테르[2-Phenethyl-2H-indazole-5-carboxylic acid methyl ester; 화합물 11]10) 2-Phenethyl-2 H -indazole-5-carboxylic acid methyl ester [2-Phenethyl-2 H -indazole-5-carboxylic acid methyl ester; Compound 11]
흰색 고체; 수율 41%, 1H NMR (500 MHz, DMSO-d 6) δ 8.39 (s, 1H), 8.31 (s, 1H), 7.79 (d, J = 9.4 Hz, 1H), 7.55 (d, J = 9.4 Hz, 1H), 7.25 - 7.18 (m, 5H), 4.75 (t, J = 7.3 Hz, 2H), 3.89 (s, 3H), 3.29 (t, J = 7.3 Hz, 2H).white solid; Yield 41%, 1H NMR (500 MHz, DMSO- d 6 ) δ 8.39 (s, 1H), 8.31 (s, 1H), 7.79 (d, J = 9.4 Hz, 1H), 7.55 (d, J = 9.4) Hz, 1H), 7.25 - 7.18 (m, 5H), 4.75 (t, J = 7.3 Hz, 2H), 3.89 (s, 3H), 3.29 (t, J = 7.3 Hz, 2H).
11) 2-(2-4-메톡시페닐에틸)-2H-인다졸-5-카르복실산 메틸 에스테르[2-(2-4-Methoxyphenylethyl)-2H-indazole-5-carboxylic acid methyl ester; 화합물 12]11) 2-(2-4-methoxyphenylethyl)-2 H -indazole-5-carboxylic acid methyl ester [2-(2-4-Methoxyphenylethyl)-2 H -indazole-5-carboxylic acid methyl ester ; Compound 12]
흰색 고체; 수율 42%, 1H NMR (500 MHz, DMSO-d 6) δ 8.37 (s, 1H), 8.33 (s, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.56 (d, J = 8.7 Hz, 1H), 7.09 (d, J = 8.6 Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 4.69 (t, J = 7.3 Hz, 2H), 3.88 (s, 3H), 3.69 (s, 3H), 3.22 (t, J = 7.3 Hz, 2H).white solid; Yield 42%, 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.37 (s, 1H), 8.33 (s, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.56 (d, J = 8.7) Hz, 1H), 7.09 (d, J = 8.6 Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 4.69 (t, J = 7.3 Hz, 2H), 3.88 (s, 3H), 3.69 ( s, 3H), 3.22 (t, J = 7.3 Hz, 2H).
12) 2-(3,5-다이플루오로벤질)-2H-인다졸-5-카르복실산 메틸 에스테르[2-(3,5-Difluorobenzyl)-2H-indazole-5-carboxylic acid methyl ester; 화합물 13]12) 2-(3,5-difluorobenzyl)-2 H -indazole-5-carboxylic acid methyl ester [2-(3,5-Difluorobenzyl)-2 H -indazole-5-carboxylic acid methyl ester ; Compound 13]
흰색 고체; 수율 38%, 1H NMR (500 MHz, DMSO-d 6) δ 8.66 (s, 1H), 8.31 (s, 1H), 7.86 (d, J = 9.4 Hz, 1H), 7.59 (d, J = 9.4 Hz, 1H), 7.21 (tt, J = 8.9 Hz, 2.3Hz, 1H), 7.11 - 7.05 (m, 2H), 5.76 (s, 2H), 3.88 (s, 3H).white solid; Yield 38%, 1H NMR (500 MHz, DMSO- d 6 ) δ 8.66 (s, 1H), 8.31 (s, 1H), 7.86 (d, J = 9.4 Hz, 1H), 7.59 (d, J = 9.4) Hz, 1H), 7.21 (tt, J = 8.9 Hz, 2.3Hz, 1H), 7.11 - 7.05 (m, 2H), 5.76 (s, 2H), 3.88 (s, 3H).
13) 2-(4-다이플루오로메톡시벤질)-2H-인다졸-5-카르복실산 메틸 에스테르[2-(4-Difluoromethoxybenzyl)-2H-indazole-5-carboxylic acid methyl ester; 화합물 14]13) 2-(4-difluoromethoxybenzyl)-2 H -indazole-5-carboxylic acid methyl ester [2-(4-Difluoromethoxybenzyl)-2 H -indazole-5-carboxylic acid methyl ester; Compound 14]
흰색 고체; 수율 39%, 1H NMR (500 MHz, DMSO-d 6) δ 8.63 (s, 1H), 8.29 (s, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.6 Hz, 2H), 7.36 (t, J = 74.0, 1H), 7.18 (d, J = 8.6), 5.72 (s, 2H), 3.88 (s, 3H).white solid; Yield 39%, 1H NMR (500 MHz, DMSO- d 6 ) δ 8.63 (s, 1H), 8.29 (s, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.6 Hz, 2H), 7.36 (t, J = 74.0, 1H), 7.18 (d, J = 8.6), 5.72 (s, 2H), 3.88 (s, 3H) .
14) 2-바이페닐-4-일메틸-2H-인다졸-5-카르복실산 메틸 에스테르[2-Biphenyl-4-ylmethyl-2H-indazole-5-carboxylic acid methyl ester; 화합물 15]14) 2-Biphenyl-4-ylmethyl-2 H -indazole-5-carboxylic acid methyl ester [2-Biphenyl-4-ylmethyl-2 H -indazole-5-carboxylic acid methyl ester; Compound 15]
흰색 고체; 수율 42%, 1H NMR (500 MHz, DMSO-d 6) δ 8.66 (s, 1H), 8.31 (s, 1H), 7.85 (d, J = 8.7 Hz, 1H), 7.71 - 7.61 (m, 4H), 7.58 (d, J = 8.7 Hz, 1H), 7.47 - 7.43 (m, 4H), 7.37 (t, J = 7.3 Hz, 1H), 5.77 (s, 2H), 3.88 (s, 3H).white solid; Yield 42%, 1H NMR (500 MHz, DMSO- d 6 ) δ 8.66 (s, 1H), 8.31 (s, 1H), 7.85 (d, J = 8.7 Hz, 1H), 7.71 - 7.61 (m, 4H) ), 7.58 (d, J = 8.7 Hz, 1H), 7.47 - 7.43 (m, 4H), 7.37 (t, J = 7.3 Hz, 1H), 5.77 (s, 2H), 3.88 (s, 3H).
15) 2-(4-아이소프로필벤질)-2H-인다졸-6-카르복실산 메틸 에스테르[2-(4-Isopropylbenzyl)-2H-indazole-6-carboxylic acid methyl ester; 화합물 16] 15) 2-(4-Isopropylbenzyl)-2 H -indazole-6-carboxylic acid methyl ester [2-(4-Isopropylbenzyl)-2 H -indazole-6-carboxylic acid methyl ester; Compound 16]
흰색 고체; 수율 36%, 1H NMR (500 MHz, CDCl3) δ 8.52 (s, 1H), 7.90 (s, 1H), 7.70 (dd, J = 8.8, 1.3 Hz, 1H), 7.64 (dd, J = 8.8, 0.8 Hz, 1H), 7.25 - 7.20 (m, 4H), 5.59 (s, 2H), 3.95 (s, 3H), 2.90 (hept, J = 6.9 Hz, 1H), 1.23 (d, J = 6.9 Hz, 6H). white solid; Yield 36%, 1H NMR (500 MHz, CDCl 3 ) δ 8.52 (s, 1H), 7.90 (s, 1H), 7.70 (dd, J = 8.8, 1.3 Hz, 1H), 7.64 (dd, J = 8.8 , 0.8 Hz, 1H), 7.25 - 7.20 (m, 4H), 5.59 (s, 2H), 3.95 (s, 3H), 2.90 (hept, J = 6.9 Hz, 1H), 1.23 (d, J = 6.9 Hz) , 6H).
16) 2-(2-(4-플루오로페닐)에틸)-2H-인다졸-6-카르복실산 메틸 에스테르[2-(2-(4-Fluorophenyl)ethyl)-2H-indazole-6-carboxylic acid methyl ester; 화합물 17] 16) 2-(2-(4-Fluorophenyl)ethyl) -2H -indazole-6-carboxylic acid methyl ester [2-(2-(4-Fluorophenyl)ethyl) -2H- indazole-6 -carboxylic acid methyl ester; Compound 17]
흰색 고체; 수율 20%, 1H NMR (500 MHz, CDCl3) δ 8.52 (s, 1H), 7.70 (dd, J = 8.6, 1.1 Hz, 2H), 7.62 (dd, J = 8.6, 0.6 Hz, 1H), 7.06 - 6.97 (m, 2H), 6.97 - 6.87 (m, 2H), 4.63 (t, J = 7.1 Hz, 2H), 3.96 (s, 3H), 3.31 (t, J = 7.1 Hz, 2H).white solid; Yield 20%, 1H NMR (500 MHz, CDCl 3 ) δ 8.52 (s, 1H), 7.70 (dd, J = 8.6, 1.1 Hz, 2H), 7.62 (dd, J = 8.6, 0.6 Hz, 1H), 7.06 - 6.97 (m, 2H), 6.97 - 6.87 (m, 2H), 4.63 (t, J = 7.1 Hz, 2H), 3.96 (s, 3H), 3.31 (t, J = 7.1 Hz, 2H).
17) 2-(3-플루오로벤질)-2H-인다졸-6-카르복실산 메틸 에스테르[2-(3-Fluorobenzyl)-2H-indazole-6-carboxylic acid methyl ester; 화합물 18]17) 2-(3-Fluorobenzyl)-2 H -indazole-6-carboxylic acid methyl ester [2-(3-Fluorobenzyl)-2 H -indazole-6-carboxylic acid methyl ester; Compound 18]
흰색 고체; 수율 39%, 1H NMR (500 MHz, CDCl3) δ 8.52 (d, J = 1.3 Hz, 1H), 7.94 (s, 1H), 7.70 (dd, J = 8.8, 1.4 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.30 (q, J = 8.0 Hz, 1H), 7.11 - 6.97 (m, 2H), 6.95 (d, J = 9.5 Hz, 1H), 5.58 (s, 2H), 3.93 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 167.5, 163.0, 148.3, 137.8, 130.6, 128.1, 124.2, 123.5, 123.3, 121.6, 121.4, 120.3, 115.5, 114.93, 57.2, 52.2.white solid; Yield 39%, 1H NMR (500 MHz, CDCl 3 ) δ 8.52 (d, J = 1.3 Hz, 1H), 7.94 (s, 1H), 7.70 (dd, J = 8.8, 1.4 Hz, 1H), 7.64 ( d, J = 8.8 Hz, 1H), 7.30 (q, J = 8.0 Hz, 1H), 7.11 - 6.97 (m, 2H), 6.95 (d, J = 9.5 Hz, 1H), 5.58 (s, 2H), 3.93 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ 167.5, 163.0, 148.3, 137.8, 130.6, 128.1, 124.2, 123.5, 123.3, 121.6, 121.4, 120.3, 115.5, 114.93, 57 .2, 52.2.
18) 2-(3-클로로벤질)-2H-인다졸-6-카르복실산 메틸 에스테르[2-(3-Chlorobenzyl)-2H-indazole-6-carboxylic acid methyl ester; 화합물 19]18) 2-(3-Chlorobenzyl)-2 H -indazole-6-carboxylic acid methyl ester [2-(3-Chlorobenzyl)-2 H -indazole-6-carboxylic acid methyl ester; Compound 19]
흰색 고체; 수율 39%, 1H NMR (500 MHz, CDCl3) δ 8.52 (s, 1H), 7.95 (s, 1H), 7.72 (dd, J = 8.8, 1.3 Hz, 1H), 7.67 (dd, J = 8.8, 0.7 Hz, 1H), 7.34 - 7.28 (m, 3H), 7.17 (d, J = 7.0 Hz, 1H), 5.60 (s, 2H), 3.95 (s, 3H).white solid; Yield 39%, 1H NMR (500 MHz, CDCl 3 ) δ 8.52 (s, 1H), 7.95 (s, 1H), 7.72 (dd, J = 8.8, 1.3 Hz, 1H), 7.67 (dd, J = 8.8 , 0.7 Hz, 1H), 7.34 - 7.28 (m, 3H), 7.17 (d, J = 7.0 Hz, 1H), 5.60 (s, 2H), 3.95 (s, 3H).
19) 2-(3-트리플루오로메틸벤질)-2H-인다졸-6-카르복실산 메틸 에스테르[2-(3-Trifluoromethylbenzyl)-2H-indazole-6-carboxylic acid methyl ester; 화합물 20]19) 2-(3-Trifluoromethylbenzyl)-2 H -indazole-6-carboxylic acid methyl ester [2-(3-Trifluoromethylbenzyl)-2 H -indazole-6-carboxylic acid methyl ester; Compound 20]
흰색 고체; 수율 36%, 1H NMR (500 MHz, CDCl3) δ 8.52 (q, J = 1.1 Hz, 1H), 7.97 (d, J = 1.1 Hz, 1H), 7.73 (dd, J = 8.7, 1.4 Hz, 1H), 7.67 (dd, J = 8.7, 1.0 Hz, 1H), 7.60 (d, J = 7.4 Hz, 1H), 7.59 - 7.57 (m, 1H), 7.52 - 7.41 (m, 2H), 5.68 (s, 2H), 3.95 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 167.5, 148.4, 136.4, 131.3, 131.3, 129.6, 128.2, 125.5, 124.7, 123.8, 124.3, 123.2, 121.8, 121.5, 120.2, 57.3, 52.2.white solid; Yield 36%, 1H NMR (500 MHz, CDCl 3 ) δ 8.52 (q, J = 1.1 Hz, 1H), 7.97 (d, J = 1.1 Hz, 1H), 7.73 (dd, J = 8.7, 1.4 Hz, 1H), 7.67 (dd, J = 8.7, 1.0 Hz, 1H), 7.60 (d, J = 7.4 Hz, 1H), 7.59 - 7.57 (m, 1H), 7.52 - 7.41 (m, 2H), 5.68 (s) , 2H), 3.95 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ 167.5, 148.4, 136.4, 131.3, 131.3, 129.6, 128.2, 125.5, 124.7, 123.8, 124.3, 123.2, 121.8, 121.5, 120 .2, 57.3, 52.2.
20) 2-(4-트리플루오로메틸벤질)-2H-인다졸-6-카르복실산 메틸 에스테르[2-(4-Trifluoromethylbenzyl)-2H-indazole-6-carboxylic acid methyl ester; 화합물 21]20) 2-(4-Trifluoromethylbenzyl)-2 H -indazole-6-carboxylic acid methyl ester [2-(4-Trifluoromethylbenzyl)-2 H -indazole-6-carboxylic acid methyl ester; Compound 21]
흰색 고체; 수율 37%, 1H NMR (500 MHz, CDCl3) δ 8.52 (d, J = 1.1 Hz, 1H), 7.97 (d, J = 1.1 Hz, 1H), 7.72 (dd, J = 8.8, 1.4 Hz, 1H), 7.66 (dd, J = 8.8, 1.0 Hz, 1H), 7.60 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 5.67 (s, 2H), 3.94 (s, 3H).white solid; Yield 37%, 1 H NMR (500 MHz, CDCl 3 ) δ 8.52 (d, J = 1.1 Hz, 1H), 7.97 (d, J = 1.1 Hz, 1H), 7.72 (dd, J = 8.8, 1.4 Hz, 1H), 7.66 (dd, J = 8.8, 1.0 Hz, 1H), 7.60 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 5.67 (s, 2H), 3.94 ( s, 3H).
21) 2-(3-메톡시벤질)-2H-인다졸-6-카르복실산 메틸 에스테르[2-(3-Methoxybenzyl)-2H-indazole-6-carboxylic acid methyl ester; 화합물 22]21) 2-(3-Methoxybenzyl)-2 H -indazole-6-carboxylic acid methyl ester [2-(3-Methoxybenzyl)-2 H -indazole-6-carboxylic acid methyl ester; Compound 22]
흰색 고체; 수율 39%, 1H NMR (500 MHz, CDCl3) δ 8.52 (d, J = 0.9 Hz, 1H), 7.91 (d, J = 0.9 Hz, 1H), 7.70 (dd, J = 8.8, 1.3 Hz, 1H), 7.64 (dd, J = 8.8, 0.6 Hz, 1H), 7.27 (t, J = 7.9 Hz, 1H), 6.91 - 6.85 (m, 2H), 6.83 (d, J = 1.7 Hz, 1H), 5.58 (s, 2H), 3.94 (s, 3H), 3.76 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 167.6, 160.1, 148.1, 136.7, 130.1, 127.9, 124.2, 123.1, 121.5, 121.4, 120.3, 120.2, 114.0, 113.8, 57.9, 55.3, 52.2.white solid; Yield 39%, 1H NMR (500 MHz, CDCl 3 ) δ 8.52 (d, J = 0.9 Hz, 1H), 7.91 (d, J = 0.9 Hz, 1H), 7.70 (dd, J = 8.8, 1.3 Hz, 1H), 7.64 (dd, J = 8.8, 0.6 Hz, 1H), 7.27 (t, J = 7.9 Hz, 1H), 6.91 - 6.85 (m, 2H), 6.83 (d, J = 1.7 Hz, 1H), 5.58 (s, 2H), 3.94 (s, 3H), 3.76 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ 167.6, 160.1, 148.1, 136.7, 130.1, 127.9, 124.2, 123.1, 121.5, 121.4, 120.3, 120.2, 114.0, 113.8, 57. 9, 55.3, 52.2.
22) 2-(3-벤질옥시벤질)-2H-인다졸-6-카르복실산 메틸 에스테르[2-(3-Benzyloxybenzyl)-2H-indazole-6-carboxylic acid methyl ester; 화합물 23]22) 2-(3-Benzyloxybenzyl)-2 H -indazole-6-carboxylic acid methyl ester [2-(3-Benzyloxybenzyl)-2 H -indazole-6-carboxylic acid methyl ester; Compound 23]
흰색 고체; 수율 42%, 1H NMR (500 MHz, CDCl3) δ 8.52 (d, J = 1.1 Hz, 1H), 7.89 (d, J = 1.1 Hz, 1H), 7.71 (dd, J = 8.8, 1.4 Hz, 1H), 7.65 (dd, J = 8.8, 0.9 Hz, 1H), 7.39 - 7.27 (m, 6H), 6.96 - 6.94 (m, 1H), 6.92 - 6.84 (m, 2H), 5.59 (s, 2H), 5.02 (s, 2H), 3.95 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 167.6, 159.2, 148.1, 136.8, 136.6, 130.1, 128.6, 128.1, 127.9, 127.5, 124.2, 123.2, 121.5, 121.4, 120.6, 120.3, 115.0, 114.7, 70.0, 57.8, 52.2.white solid; Yield 42%, 1 H NMR (500 MHz, CDCl 3 ) δ 8.52 (d, J = 1.1 Hz, 1H), 7.89 (d, J = 1.1 Hz, 1H), 7.71 (dd, J = 8.8, 1.4 Hz, 1H), 7.65 (dd, J = 8.8, 0.9 Hz, 1H), 7.39 - 7.27 (m, 6H), 6.96 - 6.94 (m, 1H), 6.92 - 6.84 (m, 2H), 5.59 (s, 2H) , 5.02 (s, 2H), 3.95 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ 167.6, 159.2, 148.1, 136.8, 136.6, 130.1, 128.6, 128.1, 127.9, 127.5, 124.2, 123.2, 121.5, 121.4, 120 .6, 120.3, 115.0, 114.7, 70.0, 57.8 , 52.2.
23) 2-(3,5-다이메톡시벤질)-2H-인다졸-6-카르복실산 메틸 에스테르[2-(3,5-Dimethoxybenzyl)-2H-indazole-6-carboxylic acid methyl ester; 화합물 24]23) 2-(3,5-dimethoxybenzyl)-2 H -indazole-6-carboxylic acid methyl ester [2-(3,5-Dimethoxybenzyl)-2 H -indazole-6-carboxylic acid methyl ester ; Compound 24]
흰색 고체; 수율 40%, 1H NMR (500 MHz, CDCl3) δ 8.51 (d, J = 1.1 Hz, 1H), 7.92 (d, J = 1.1 Hz, 1H), 7.69 (dt, J = 8.8, 1.4 Hz, 1H), 7.65 - 7.63 (m, 1H), 6.46 - 6.37 (m, 3H), 5.54 - 5.52 (m, 2H), 3.94 (q, J = 1.4 Hz, 3H), 3.74 (q, J = 1.4 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 167.6, 161.3, 148.1, 137.4, 127.9, 124.2, 123.2, 121.5, 121.4, 120.3, 106.2, 100.3, 58.0, 55.4, 52.2.white solid; Yield 40%, 1 H NMR (500 MHz, CDCl 3 ) δ 8.51 (d, J = 1.1 Hz, 1H), 7.92 (d, J = 1.1 Hz, 1H), 7.69 (dt, J = 8.8, 1.4 Hz, 1H), 7.65 - 7.63 (m, 1H), 6.46 - 6.37 (m, 3H), 5.54 - 5.52 (m, 2H), 3.94 (q, J = 1.4 Hz, 3H), 3.74 (q, J = 1.4 Hz) , 6H); 13 C NMR (125 MHz, CDCL 3 ) δ 167.6, 161.3, 148.1, 137.4, 127.9, 124.2, 123.2, 121.5, 121.4, 120.3, 106.2, 100.3, 58.0, 55.4, 52.2.
24) 2-(3-페녹시벤질)-2H-인다졸-6-카르복실산 메틸 에스테르[2-(3-Phenoxybenzyl)-2H-indazole-6-carboxylic acid methyl ester; 화합물 25]24) 2-(3-Phenoxybenzyl)-2 H -indazole-6-carboxylic acid methyl ester [2-(3-Phenoxybenzyl)-2 H -indazole-6-carboxylic acid methyl ester; Compound 25]
흰색 고체; 수율 32%, 1H NMR (500 MHz, CDCl3) δ 8.51 (d, J = 1.1 Hz, 1H), 7.92 (d, J = 1.1 Hz, 1H), 7.70 (dd, J = 8.8, 1.4 Hz, 1H), 7.64 (dd, J = 8.8, 0.9 Hz, 1H), 7.31 - 7.27 (m, 3H), 7.14 - 7.06 (m, 1H), 7.02 - 6.96 (m, 3H), 6.96 - 6.90 (m, 2H), 5.57 (s, 2H), 3.93 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 167.5, 158.0, 156.6, 148.2, 137.3, 130.4, 129.9, 128.0, 124.2, 123.7, 123.2, 122.5, 121.5, 121.4, 120.2, 119.2, 118.5, 118.2, 57.6, 52.2.white solid; Yield 32%, 1 H NMR (500 MHz, CDCl 3 ) δ 8.51 (d, J = 1.1 Hz, 1H), 7.92 (d, J = 1.1 Hz, 1H), 7.70 (dd, J = 8.8, 1.4 Hz, 1H), 7.64 (dd, J = 8.8, 0.9 Hz, 1H), 7.31 - 7.27 (m, 3H), 7.14 - 7.06 (m, 1H), 7.02 - 6.96 (m, 3H), 6.96 - 6.90 (m, 2H), 5.57 (s, 2H), 3.93 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ 167.5, 158.0, 156.6, 148.2, 137.3, 130.4, 129.9, 128.0, 124.2, 123.7, 123.2, 122.5, 121.5, 121.4, 120 .2, 119.2, 118.5, 118.2, 57.6, 52.2 .
25) 2-피리딘-3-일메틸-2H-인다졸-6-카르복실산 메틸 에스테르[2-Pyridin-3-ylmethyl-2H-indazole-6-carboxylic acid methyl ester; 화합물 74]25) 2-Pyridin-3-ylmethyl-2 H -indazole-6-carboxylic acid methyl ester [2-Pyridin-3-ylmethyl-2 H -indazole-6-carboxylic acid methyl ester; Compound 74]
흰색 고체; 수율 51%, 1H NMR (500 MHz, CDCl3) δ 8.72 - 8.55 (m, 2H), 8.51 (d, J = 1.0 Hz, 1H), 7.98 (d, J = 0.6 Hz, 1H), 7.72 (dd, J = 8.8, 1.3 Hz, 1H), 7.67 (dd, J = 8.8, 0.8 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.33 - 7.27 (m, 1H), 5.65 (s, 2H), 3.95 (s, 3H).white solid; Yield 51%, 1H NMR (500 MHz, CDCl3) δ 8.72 - 8.55 (m, 2H), 8.51 (d, J = 1.0 Hz, 1H), 7.98 (d, J = 0.6 Hz, 1H), 7.72 (dd , J = 8.8, 1.3 Hz, 1H), 7.67 (dd, J = 8.8, 0.8 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.33 - 7.27 (m, 1H), 5.65 (s, 2H), 3.95 (s, 3H).
2. 2. N2N2 치환된 2 substituted 2 HH -인다졸-6-카르복실산 합성(화합물 26 - 화합물 49, 화합물 75)-Indazole-6-carboxylic acid synthesis (Compound 26 - Compound 49, Compound 75)
N2 치환된 2H-인다졸-6-카르복실산 메틸 에스테르(화합물 2-25 및 74, 1 mmol)을 메탄올(5-10 ml)에서 용해시키고, 2N NaOH 용액(1-2 ml)을 천천히 첨가하였다. 반응혼합물을 실온에서 6-12시간 동안 교반한 후, 물에 넣고 2N HCl로 중화시킨 후 침전물을 여과하고 건조하여 카르복실산 유도체(화합물 26-49, 화합물 75)를 얻었다. N 2 substituted 2 H -indazole-6-carboxylic acid methyl ester (compounds 2-25 and 74, 1 mmol) was dissolved in methanol (5-10 ml) and 2N NaOH solution (1-2 ml). It was added slowly. The reaction mixture was stirred at room temperature for 6-12 hours, added to water, neutralized with 2N HCl, and the precipitate was filtered and dried to obtain carboxylic acid derivatives (Compound 26-49, Compound 75).
1) 2-벤질-2H-인다졸-5-카르복실산[2-Benzyl-2H-indazole-5-carboxylic acid; 화합물 26]1) 2-Benzyl-2 H -indazole-5-carboxylic acid [2-Benzyl-2 H -indazole-5-carboxylic acid; Compound 26]
흰색 고체; 수율 75%, 1H NMR (500 MHz, DMSO-d 6) δ 12.88 (s, 1H), 8.60 (s, 1H), 8.27 (s, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.41 - 7.28 (m, 5H), 5.71 (s, 2H).white solid; Yield 75%, 1H NMR (500 MHz, DMSO- d 6 ) δ 12.88 (s, 1H), 8.60 (s, 1H), 8.27 (s, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.41 - 7.28 (m, 5H), 5.71 (s, 2H).
2) 2-(4-메톡시벤질)-2H-인다졸-5-카르복실산[2-(4-Methoxybenzyl)-2H-indazole-5-carboxylic acid; 화합물 27]2) 2-(4-Methoxybenzyl)-2 H -indazole-5-carboxylic acid [2-(4-Methoxybenzyl)-2 H -indazole-5-carboxylic acid; Compound 27]
흰색 고체; 수율 64%, 1H NMR (500 MHz, DMSO-d 6) δ 12.87 (s, 1H), 8.54 (s, 1H), 8.26 (s, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.56 (d, J = 8.7 Hz, 1H), 7.35 (d, J = 8.2 Hz, 2H), 6.93 (d, J = 8.2 Hz, 2H), 5.62 (s, 2H), 3.73 (s, 3H).white solid; Yield 64%, 1H NMR (500 MHz, DMSO- d 6 ) δ 12.87 (s, 1H), 8.54 (s, 1H), 8.26 (s, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.56 (d, J = 8.7 Hz, 1H), 7.35 (d, J = 8.2 Hz, 2H), 6.93 (d, J = 8.2 Hz, 2H), 5.62 (s, 2H), 3.73 (s, 3H).
3) 2-(4-메틸벤질)-2H-인다졸-5-카르복실산[2-(4-Methylbenzyl)-2H-indazole-5-carboxylic acid; 화합물 28]3) 2-(4-Methylbenzyl)-2 H -indazole-5-carboxylic acid [2-(4-Methylbenzyl)-2 H -indazole-5-carboxylic acid; Compound 28]
흰색 고체; 수율 69%, 1H NMR (500 MHz, DMSO-d 6) δ 12.88 (s, 1H), 8.55 (s, 1H), 8.26 (s, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.56 (d, J = 8.7 Hz, 1H), 7.26 (d, J = 7.9 Hz, 2H), 7.17 (d, J = 7.9 Hz, 2H), 5.65 (s, 2H), 2.27 (s, 3H).white solid; Yield 69%, 1H NMR (500 MHz, DMSO- d 6 ) δ 12.88 (s, 1H), 8.55 (s, 1H), 8.26 (s, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.56 (d, J = 8.7 Hz, 1H), 7.26 (d, J = 7.9 Hz, 2H), 7.17 (d, J = 7.9 Hz, 2H), 5.65 (s, 2H), 2.27 (s, 3H).
4) 2-(4-플루오로벤질)-2H-인다졸-5-카르복실산[2-(4-Fluorobenzyl)-2H-indazole-5-carboxylic acid; 화합물 29]4) 2-(4-Fluorobenzyl)-2 H -indazole-5-carboxylic acid [2-(4-Fluorobenzyl)-2 H -indazole-5-carboxylic acid; Compound 29]
흰색 고체; 수율 77%, 1H NMR (500 MHz, DMSO-d 6) δ 12.89 (s, 1H), 8.60 (s, 1H), 8.27 (s, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.45 - 7.41 (m, 2H), 7.20 (t, J = 8.9 Hz, 2H), 5.70 (s, 2H).white solid; Yield 77%, 1H NMR (500 MHz, DMSO- d 6 ) δ 12.89 (s, 1H), 8.60 (s, 1H), 8.27 (s, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.45 - 7.41 (m, 2H), 7.20 (t, J = 8.9 Hz, 2H), 5.70 (s, 2H).
5) 2-(4-클로로벤질)-2H-인다졸-5-카르복실산[2-(4-Chlorobenzyl)-2H-indazole-5-carboxylic acid; 화합물 30]5) 2-(4-Chlorobenzyl)-2 H -indazole-5-carboxylic acid [2-(4-Chlorobenzyl)-2 H -indazole-5-carboxylic acid; Compound 30]
흰색 고체; 수율 71%, 1H NMR (500 MHz, DMSO-d 6) δ 12.90 (s, 1H), 8.61 (s, 1H), 8.26 (s, 1H), 7.81 (d, J = 9.4 Hz, 1H), 7.57 (d, J = 9.4 Hz, 1H), 7.44 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 8.5 Hz, 2H), 5.72 (s, 2H).white solid; Yield 71%, 1H NMR (500 MHz, DMSO- d 6 ) δ 12.90 (s, 1H), 8.61 (s, 1H), 8.26 (s, 1H), 7.81 (d, J = 9.4 Hz, 1H), 7.57 (d, J = 9.4 Hz, 1H), 7.44 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 8.5 Hz, 2H), 5.72 (s, 2H).
6) 2-(4-브로모벤질)-2H-인다졸-5-카르복실산[2-(4-Bromobenzyl)-2H-indazole-5-carboxylic acid; 화합물 31]6) 2-(4-Bromobenzyl)-2 H -indazole-5-carboxylic acid [2-(4-Bromobenzyl)-2 H -indazole-5-carboxylic acid; Compound 31]
흰색 고체; 수율 73%, 1H NMR (500 MHz, DMSO-d 6) δ 12.88 (s, 1H), 8.60 (s, 1H), 8.26 (s, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.58 - 7.56 (m, 3H), 7.31 (d, J = 8.4 Hz, 2H), 5.70 (s, 2H).white solid; Yield 73%, 1H NMR (500 MHz, DMSO- d 6 ) δ 12.88 (s, 1H), 8.60 (s, 1H), 8.26 (s, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.58 - 7.56 (m, 3H), 7.31 (d, J = 8.4 Hz, 2H), 5.70 (s, 2H).
7) 2-(3-트리플루오로메톡시벤질)-2H-인다졸-5-카르복실산[2-(3-Trifluoromethoxybenzyl)-2H-indazole-5-carboxylic acid; 화합물 32]7) 2-(3-Trifluoromethoxybenzyl)-2 H -indazole-5-carboxylic acid [2-(3-Trifluoromethoxybenzyl)-2 H -indazole-5-carboxylic acid; Compound 32]
흰색 고체; 수율 79%, 1H NMR (500 MHz, DMSO-d 6) δ 12.90 (s, 1H), 8.44 (s, 1H), 8.41 (s, 1H), 7.80 (d, J = 9.5 Hz, 1H), 7.71 (d, J = 9.5 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.29 - 7.25 (m, 2H), 5.76 (s, 3H).white solid; Yield 79%, 1H NMR (500 MHz, DMSO- d 6 ) δ 12.90 (s, 1H), 8.44 (s, 1H), 8.41 (s, 1H), 7.80 (d, J = 9.5 Hz, 1H), 7.71 (d, J = 9.5 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.29 - 7.25 (m, 2H), 5.76 (s, 3H) ).
8) 2-(4-트리플루오로메톡시벤질)-2H-인다졸-5-카르복실산[2-(4-Trifluoromethoxybenzyl)-2H-indazole-5-carboxylic acid; 화합물 33]8) 2-(4-Trifluoromethoxybenzyl)-2 H -indazole-5-carboxylic acid [2-(4-Trifluoromethoxybenzyl)-2 H -indazole-5-carboxylic acid; Compound 33]
흰색 고체; 수율 69%, 1H NMR (500 MHz, DMSO-d 6) δ 12.90 (s, 1H), 8.64 (s, 1H), 8.27 (s, 1H), 7.81 (d, J = 9.4 Hz, 1H), 7.57 (d, J = 9.4 Hz, 1H), 7.48 (d, J = 8.7 Hz, 2H), 7.37 (d, J = 8.7 Hz, 2H), 5.76 (s, 2H).white solid; Yield 69%, 1H NMR (500 MHz, DMSO- d 6 ) δ 12.90 (s, 1H), 8.64 (s, 1H), 8.27 (s, 1H), 7.81 (d, J = 9.4 Hz, 1H), 7.57 (d, J = 9.4 Hz, 1H), 7.48 (d, J = 8.7 Hz, 2H), 7.37 (d, J = 8.7 Hz, 2H), 5.76 (s, 2H).
9) 2-나프탈렌-2-일메틸-2H-인다졸-5-카르복실산[2-Naphthalen-2-ylmethyl-2H-indazole-5-carboxylic acid; 화합물 34]9) 2-Naphthalen-2-ylmethyl-2 H -indazole-5-carboxylic acid [2-Naphthalen-2-ylmethyl-2 H -indazole-5-carboxylic acid; Compound 34]
흰색 고체; 수율 71%, 1H NMR (500 MHz, DMSO-d 6) δ 12.89 (s, 1H), 8.66 (s, 1H), 8.28 (s, 1H), 7.92 - 7.90 (m, 4H), 7.82 (d, J = 8.7 Hz, 1H), 7.64 - 7.45 (m, 4H), 5.88 (s, 2H).white solid; Yield 71%, 1H NMR (500 MHz, DMSO- d 6 ) δ 12.89 (s, 1H), 8.66 (s, 1H), 8.28 (s, 1H), 7.92 - 7.90 (m, 4H), 7.82 (d) , J = 8.7 Hz, 1H), 7.64 - 7.45 (m, 4H), 5.88 (s, 2H).
10) 2-페네틸-2H-인다졸-5-카르복실산[2-Phenethyl-2H-indazole-5-carboxylic acid; 화합물 35]10) 2-Phenethyl-2 H -indazole-5-carboxylic acid [2-Phenethyl-2 H -indazole-5-carboxylic acid; Compound 35]
흰색 고체; 수율 79%, 1H NMR (500 MHz, DMSO-d 6) δ 12.88 (s, 1H), 8.37 (s, 1H), 8.29 (s, 1H), 7.75 (d, J = 9.2 Hz, 1H), 7.55 (d, J = 9.2 Hz, 1H), 7.30 - 7.22 (m, 2H), 7.21 - 7.19 (m, 3H), 4.74 (t, J = 7.3 Hz, 2H), 3.29 (t, J = 7.3 Hz, 2H).white solid; Yield 79%, 1H NMR (500 MHz, DMSO- d 6 ) δ 12.88 (s, 1H), 8.37 (s, 1H), 8.29 (s, 1H), 7.75 (d, J = 9.2 Hz, 1H), 7.55 (d, J = 9.2 Hz, 1H), 7.30 - 7.22 (m, 2H), 7.21 - 7.19 (m, 3H), 4.74 (t, J = 7.3 Hz, 2H), 3.29 (t, J = 7.3 Hz) , 2H).
11) 2-[2-(4-메톡시페닐에틸)]-2H-인다졸-5-카르복실산[2-[2-(4-Methoxyphenylethyl)]-2H-indazole-5-carboxylic acid; 화합물 36]11) 2-[2-(4-Methoxyphenylethyl)]-2 H -indazole-5-carboxylic acid [2-[2-(4-Methoxyphenylethyl)]-2 H -indazole-5-carboxylic acid ; Compound 36]
흰색 고체; 수율 82%, 1H NMR (500 MHz, DMSO-d 6) δ 12.90 (s, 1H), 8.36 (s, 1H), 8.29 (s, 1H), 7.75 (d, J = 8.7 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.09 (d, J = 8.6 Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 4.68 (t, J = 7.3 Hz, 2H), 3.69 (s, 3H), 3.22 (t, J = 7.3 Hz, 2H).white solid; Yield 82%, 1H NMR (500 MHz, DMSO- d 6 ) δ 12.90 (s, 1H), 8.36 (s, 1H), 8.29 (s, 1H), 7.75 (d, J = 8.7 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.09 (d, J = 8.6 Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 4.68 (t, J = 7.3 Hz, 2H), 3.69 ( s, 3H), 3.22 (t, J = 7.3 Hz, 2H).
12) 2-(3,5-다이플루오로벤질)-2H-인다졸-5-카르복실산[2-(3,5-Difluorobenzyl)-2H-indazole-5-carboxylic acid; 화합물 37]12) 2-(3,5-difluorobenzyl)-2 H -indazole-5-carboxylic acid [2-(3,5-Difluorobenzyl)-2 H -indazole-5-carboxylic acid; Compound 37]
흰색 고체; 수율 68%, 1H NMR (500 MHz, DMSO-d 6) δ 12.96 (s, 1H), 8.65 (s, 1H), 8.28 (s, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.58 (d, J = 8.7 Hz, 1H), 7.23 (tt, J = 8.9 Hz, 2.3Hz, 1H), 7.09 - 7.05 (m, 2H), 5.75 (s, 2H).white solid; Yield 68%, 1H NMR (500 MHz, DMSO- d 6 ) δ 12.96 (s, 1H), 8.65 (s, 1H), 8.28 (s, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.58 (d, J = 8.7 Hz, 1H), 7.23 (tt, J = 8.9 Hz, 2.3Hz, 1H), 7.09 - 7.05 (m, 2H), 5.75 (s, 2H).
13) 2-(4-다이플루오로메톡시벤질)-2H-인다졸-5-카르복실산[2-(4-Difluoromethoxybenzyl)-2H-indazole-5-carboxylic acid; 화합물 38]13) 2-(4-difluoromethoxybenzyl)-2 H -indazole-5-carboxylic acid [2-(4-Difluoromethoxybenzyl)-2 H -indazole-5-carboxylic acid; Compound 38]
흰색 고체; 수율 60%, 1H NMR (500 MH DMSO-d 6) δ 12.89 (s, 1H), 8.60 (s, 1H), 8.27 (s, 1H), 7.81 (d, J = 8.7 Hz, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.44 (d, J = 8.6 Hz, 2H), 7.22 (t, J = 74.0), 7.20 (d, J = 8.6 Hz, 2H), 5.71 (s, 2H).white solid; Yield 60%, 1 H NMR (500 MH DMSO- d 6 ) δ 12.89 (s, 1H), 8.60 (s, 1H), 8.27 (s, 1H), 7.81 (d, J = 8.7 Hz, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.44 (d, J = 8.6 Hz, 2H), 7.22 (t, J = 74.0), 7.20 (d, J = 8.6 Hz, 2H), 5.71 (s, 2H) .
14) 2-바이페닐-4-일메틸-2H-인다졸-5-카르복실산[2-Biphenyl-4-ylmethyl-2H-indazole-5-carboxylic acid; 화합물 39]14) 2-Biphenyl-4-ylmethyl-2 H -indazole-5-carboxylic acid [2-Biphenyl-4-ylmethyl-2 H -indazole-5-carboxylic acid; Compound 39]
흰색 고체; 수율 71%, 1H NMR (500 MHz, DMSO-d 6) δ 12.90 (s, 1H), 8.64 (s, 1H), 8.29 (s, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.67 - 7.62 (m, 4H), 7.58 (d, J = 9.9 Hz, 1H), 7.48 - 7.44 (m, 4H), 7.36 (t, J = 7.4 Hz, 1H), 5.76 (s, 2H).white solid; Yield 71%, 1H NMR (500 MHz, DMSO- d 6 ) δ 12.90 (s, 1H), 8.64 (s, 1H), 8.29 (s, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.67 - 7.62 (m, 4H), 7.58 (d, J = 9.9 Hz, 1H), 7.48 - 7.44 (m, 4H), 7.36 (t, J = 7.4 Hz, 1H), 5.76 (s, 2H).
15) 2-(4-아이소프로필벤질)-2H-인다졸-6-카르복실산[2-(4-Isopropylbenzyl)-2H-indazole-6-carboxylic acid; 화합물 40] 15) 2-(4-Isopropylbenzyl)-2 H -indazole-6-carboxylic acid [2-(4-Isopropylbenzyl)-2 H -indazole-6-carboxylic acid; Compound 40]
흰색 고체; 수율 96%, 1H NMR (500 MHz, DMSO-d 6) δ 12.85 (s, 1H), 8.56 (s, 1H), 8.24 (s, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.28 (d, J = 8.1 Hz, 2H), 7.22 (d, J = 8.1 Hz, 2H), 5.64 (s, 2H), 2.90 - 2.81 (m, 1H), 1.16 (d, J = 6.9 Hz, 6H).white solid; Yield 96%, 1H NMR (500 MHz, DMSO- d 6 ) δ 12.85 (s, 1H), 8.56 (s, 1H), 8.24 (s, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.28 (d, J = 8.1 Hz, 2H), 7.22 (d, J = 8.1 Hz, 2H), 5.64 (s, 2H), 2.90 - 2.81 (m, 1H) ), 1.16 (d, J = 6.9 Hz, 6H).
16) 2-[2-(4-플루오로페닐에틸)]-2H-인다졸-6-카르복실산[2-[2-(4-Fluorophenylethyl)]-2H-indazole-6-carboxylic acid; 화합물 41] 16) 2-[2-(4-Fluorophenylethyl)]-2 H -indazole-6-carboxylic acid [2-[2-(4-Fluorophenylethyl)]-2 H -indazole-6-carboxylic acid ; Compound 41]
흰색 고체; 수율 61%, 1H NMR (500 MHz, DMSO-d 6) δ 12.88 (s, 1H), 8.35 (s, 1H), 8.27 (s, 1H), 7.75 (d, J = 8.7 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.21 (dd, J = 8.3, 5.7 Hz, 2H), 7.07 (t, J = 8.3 Hz, 2H), 4.72 (t, J = 7.2 Hz, 2H), 3.28 (t, J = 7.2 Hz, 2H).white solid; Yield 61%, 1H NMR (500 MHz, DMSO- d 6 ) δ 12.88 (s, 1H), 8.35 (s, 1H), 8.27 (s, 1H), 7.75 (d, J = 8.7 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.21 (dd, J = 8.3, 5.7 Hz, 2H), 7.07 (t, J = 8.3 Hz, 2H), 4.72 (t, J = 7.2 Hz, 2H), 3.28 (t, J = 7.2 Hz, 2H).
17) 2-(3-플루오로벤질)-2H-인다졸-6-카르복실산[2-(3-Fluorobenzyl)-2H-indazole-6-carboxylic acid; 화합물 42]17) 2-(3-Fluorobenzyl)-2 H -indazole-6-carboxylic acid [2-(3-Fluorobenzyl)-2 H -indazole-6-carboxylic acid; Compound 42]
흰색 고체; 수율 83%,1H NMR (500 MHz, DMSO-d 6) δ 12.90 (s, 1H), 8.62 (s, 1H), 8.27 (s, 1H), 7.81 (d, J = 8.7 Hz, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.40 (q, J = 7.5 Hz, 1H), 7.27 - 7.05 (m, 3H), 5.73 (s, 2H); 13C NMR (125 MHz, DMSO-d 6) δ 168.2, 162.6, 148.0, 139.8, 131.2, 128.8, 125.4, 124.5, 124.0, 121.4, 121.2, 120.5, 115.4, 115.2, 56.4.white solid; Yield 83%, 1H NMR (500 MHz, DMSO- d 6 ) δ 12.90 (s, 1H), 8.62 (s, 1H), 8.27 (s, 1H), 7.81 (d, J = 8.7 Hz, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.40 (q, J = 7.5 Hz, 1H), 7.27 - 7.05 (m, 3H), 5.73 (s, 2H); 13 C NMR (125 MHz, DMSO- d 6 ) δ 168.2, 162.6, 148.0, 139.8, 131.2, 128.8, 125.4, 124.5, 124.0, 121.4, 121.2, 120.5, 115.4, 115.2, 5 6.4.
18) 2-(3-클로로벤질)-2H-인다졸-6-카르복실산[2-(3-Chlorobenzyl)-2H-indazole-6-carboxylic acid; 화합물 43]18) 2-(3-Chlorobenzyl)-2 H -indazole-6-carboxylic acid [2-(3-Chlorobenzyl)-2 H -indazole-6-carboxylic acid; Compound 43]
흰색 고체; 수율 92%, 1H NMR (500 MHz, DMSO-d 6) δ 12.90 (s, 1H), 8.63 (s, 1H), 8.26 (s, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.56 (dd, J = 8.8, 1.2 Hz, 1H), 7.42 (s, 1H), 7.41 - 7.33 (m, 2H), 7.33 - 7.25 (m, 1H), 5.72 (s, 2H); 13C NMR (125 MHz, DMSO-d 6) δ 168.2, 148.0, 139.4, 133.6, 131.1, 128.7, 128.5, 128.3, 127.2, 125.4, 124.0, 121.5, 121.2, 120.5, 98.7, 56.3.white solid; Yield 92%, 1H NMR (500 MHz, DMSO- d 6 ) δ 12.90 (s, 1H), 8.63 (s, 1H), 8.26 (s, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.56 (dd, J = 8.8, 1.2 Hz, 1H), 7.42 (s, 1H), 7.41 - 7.33 (m, 2H), 7.33 - 7.25 (m, 1H), 5.72 (s, 2H); 13 C NMR (125 MHz, DMSO- d 6 ) δ 168.2, 148.0, 139.4, 133.6, 131.1, 128.7, 128.5, 128.3, 127.2, 125.4, 124.0, 121.5, 121.2, 120.5, 9 8.7, 56.3.
19) 2-(3-트리플루오로메틸벤질)-2H-인다졸-6-카르복실산[2-(3-Trifluoromethylbenzyl)-2H-indazole-6-carboxylic acid; 화합물 44]19) 2-(3-Trifluoromethylbenzyl)-2 H -indazole-6-carboxylic acid [2-(3-Trifluoromethylbenzyl)-2 H -indazole-6-carboxylic acid; Compound 44]
흰색 고체; 수율 97%, 1H NMR (500 MHz, DMSO-d 6) δ 12.90 (s, 1H), 8.66 (s, 1H), 8.26 (s, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.77 (s, 1H), 7.72 - 7.68 (m, 1H), 7.64 - 7.53 (m, 3H), 5.83 (s, 2H); 13C NMR (125 MHz, DMSO-d 6) δ 168.2, 148.1, 141.3, 138.5, 132.7, 130.3, 129.7, 128.8, 125.6, 125.3, 125.1, 124.0, 121.5, 121.2, 120.5, 56.3.white solid; Yield 97%, 1H NMR (500 MHz, DMSO- d 6 ) δ 12.90 (s, 1H), 8.66 (s, 1H), 8.26 (s, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.77 (s, 1H), 7.72 - 7.68 (m, 1H), 7.64 - 7.53 (m, 3H), 5.83 (s, 2H); 13 C NMR (125 MHz, DMSO- d 6 ) δ 168.2, 148.1, 141.3, 138.5, 132.7, 130.3, 129.7, 128.8, 125.6, 125.3, 125.1, 124.0, 121.5, 121.2, 1 20.5, 56.3.
20) 2-(4-트리플루오로메틸벤질)-2H-인다졸-6-카르복실산[2-(4-Trifluoromethylbenzyl)-2H-indazole-6-carboxylic acid; 화합물 45]20) 2-(4-Trifluoromethylbenzyl) -2H -indazole-6-carboxylic acid [2-(4-Trifluoromethylbenzyl) -2H- indazole-6-carboxylic acid; Compound 45]
흰색 고체; 수율 93%, 1H NMR (500 MHz, DMSO-d 6) δ 12.91 (s, 1H), 8.65 (s, 1H), 8.26 (s, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 8.2 Hz, 2H), 7.57 (dd, J = 8.8, 1.2 Hz, 1H), 7.51 (d, J = 8.1 Hz, 2H), 5.83 (s, 2H); 13C NMR (125 MHz, DMSO-d 6) δ 168.2, 148.1, 141.8, 141.8, 129.1, 128.8, 126.0, 125.6, 124.0, 121.6, 121.5, 121.2, 120.5, 56.4.white solid; Yield 93%, 1H NMR (500 MHz, DMSO- d 6 ) δ 12.91 (s, 1H), 8.65 (s, 1H), 8.26 (s, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 8.2 Hz, 2H), 7.57 (dd, J = 8.8, 1.2 Hz, 1H), 7.51 (d, J = 8.1 Hz, 2H), 5.83 (s, 2H); 13 C NMR (125 MHz, DMSO- d 6 ) δ 168.2, 148.1, 141.8, 141.8, 129.1, 128.8, 126.0, 125.6, 124.0, 121.6, 121.5, 121.2, 120.5, 56.4.
21) 2-(3-메톡시벤질)-2H-인다졸-6-카르복실산[2-(3-Methoxybenzyl)-2H-indazole-6-carboxylic acid; 화합물 46]21) 2-(3-Methoxybenzyl)-2 H -indazole-6-carboxylic acid [2-(3-Methoxybenzyl)-2 H -indazole-6-carboxylic acid; Compound 46]
흰색 고체; 수율 67%, 1H NMR (500 MHz, DMSO-d 6) δ 12.86 (s, 1H), 8.57 (s, 1H), 8.26 (s, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.56 (d, J = 8.6 Hz, 1H), 7.27 (t, J = 7.6 Hz, 1H), 6.98 - 6.83 (m, 3H), 5.66 (s, 2H), 3.73 (s, 3H); 13C NMR (125 MHz, DMSO-d 6) δ 159.9, 147.9, 138.5, 130.3, 125.2, 125.1, 124.0, 121.4, 121.1, 121.1, 120.6, 120.5, 117.5, 114.3, 113.8, 57.0, 55.6.white solid; Yield 67%, 1H NMR (500 MHz, DMSO- d 6 ) δ 12.86 (s, 1H), 8.57 (s, 1H), 8.26 (s, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.56 (d, J = 8.6 Hz, 1H), 7.27 (t, J = 7.6 Hz, 1H), 6.98 - 6.83 (m, 3H), 5.66 (s, 2H), 3.73 (s, 3H); 13 C NMR (125 MHz, DMSO- d 6 ) δ 159.9, 147.9, 138.5, 130.3, 125.2, 125.1, 124.0, 121.4, 121.1, 121.1, 120.6, 120.5, 117.5, 114.3, 1 13.8, 57.0, 55.6.
22) 2-(3-벤질옥시벤질)-2H-인다졸-6-카르복실산[2-(3-Benzyloxybenzyl)-2H-indazole-6-carboxylic acid; 화합물 47]22) 2-(3-Benzyloxybenzyl)-2 H -indazole-6-carboxylic acid [2-(3-Benzyloxybenzyl)-2 H -indazole-6-carboxylic acid; Compound 47]
흰색 고체; 수율 98%, 1H NMR (500 MHz, DMSO-d 6) δ 12.90 (s, 1H), 8.57 (s, 1H), 8.27 (s, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.45 - 7.18 (m, 6H), 7.01 (s, 1H), 6.93 (dd, J = 24.9, 7.7 Hz, 2H), 5.66 (s, 2H), 5.06 (s, 2H); 13C NMR (125 MHz, DMSO-d 6) δ 168.3, 158.9, 147.9, 138.5, 137.3, 130.3, 128.9, 128.3, 128.2, 125.2, 124.0, 121.4, 121.1, 120.8, 120.6, 115.2, 114.6, 69.7, 57.0.white solid; Yield 98%, 1H NMR (500 MHz, DMSO- d 6 ) δ 12.90 (s, 1H), 8.57 (s, 1H), 8.27 (s, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.45 - 7.18 (m, 6H), 7.01 (s, 1H), 6.93 (dd, J = 24.9, 7.7 Hz, 2H), 5.66 (s, 2H), 5.06 (s, 2H); 13 C NMR (125 MHz, DMSO- d 6 ) δ 168.3, 158.9, 147.9, 138.5, 137.3, 130.3, 128.9, 128.3, 128.2, 125.2, 124.0, 121.4, 121.1, 120.8, 1 20.6, 115.2, 114.6, 69.7, 57.0 .
23) 2-(3,5-다이메톡시벤질)-2H-인돌-6-카르복실산[2-(3,5-Dimethoxybenzyl)-2H-indazole-6-carboxylic acid; 화합물 48]23) 2-(3,5-dimethoxybenzyl)-2 H -indole-6-carboxylic acid [2-(3,5-Dimethoxybenzyl)-2 H -indazole-6-carboxylic acid; Compound 48]
흰색 고체; 수율 87%, 1H NMR (500 MHz, DMSO-d 6) δ 12.90 (s, 1H), 8.57 (s, 1H), 8.27 (s, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.62 - 7.51 (m, 1H), 6.51 (d, J = 2.1 Hz, 2H), 6.45 (t, J = 2.1 Hz, 1H), 5.61 (s, 2H), 3.70 (s, 6H); 13C NMR (125 MHz, DMSO-d 6) δ 168.3, 161.1, 147.9, 139.1, 128.6, 125.2, 124.0, 121.4, 121.1, 120.6, 106.7, 99.9, 57.1, 55.7.white solid; Yield 87%, 1H NMR (500 MHz, DMSO- d 6 ) δ 12.90 (s, 1H), 8.57 (s, 1H), 8.27 (s, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.62 - 7.51 (m, 1H), 6.51 (d, J = 2.1 Hz, 2H), 6.45 (t, J = 2.1 Hz, 1H), 5.61 (s, 2H), 3.70 (s, 6H); 13 C NMR (125 MHz, DMSO- d 6 ) δ 168.3, 161.1, 147.9, 139.1, 128.6, 125.2, 124.0, 121.4, 121.1, 120.6, 106.7, 99.9, 57.1, 55.7.
24) 2-(3-페녹시벤질)-2H-인다졸-6-카르복실산[2-(3-Phenoxybenzyl)-2H-indazole-6-carboxylic acid; 화합물 49]24) 2-(3-Phenoxybenzyl)-2 H -indazole-6-carboxylic acid [2-(3-Phenoxybenzyl)-2 H -indazole-6-carboxylic acid; Compound 49]
흰색 고체; 수율 99%, 1H NMR (500 MHz, DMSO-d 6) δ 12.91 (s, 1H), 8.59 (s, 1H), 8.25 (s, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.56 (d, J = 8.7 Hz, 1H), 7.43 - 7.30 (m, 3H), 7.14 (t, J = 7.4 Hz, 1H), 7.07 (d, J = 7.7 Hz, 1H), 7.05 - 6.94 (m, 3H), 6.92 (dd, J = 8.1, 2.0 Hz, 1H), 5.70 (s, 2H); 13C NMR (125 MHz, DMSO-d 6) δ 168.3, 157.3, 156.7, 148.0, 139.3, 130.8, 130.6, 125.3, 124.2, 124.0, 123.3, 121.4, 121.2, 121.1, 120.5, 119.3, 118.5, 118.3, 56.6.white solid; Yield 99%, 1H NMR (500 MHz, DMSO- d 6 ) δ 12.91 (s, 1H), 8.59 (s, 1H), 8.25 (s, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.56 (d, J = 8.7 Hz, 1H), 7.43 - 7.30 (m, 3H), 7.14 (t, J = 7.4 Hz, 1H), 7.07 (d, J = 7.7 Hz, 1H), 7.05 - 6.94 (m , 3H), 6.92 (dd, J = 8.1, 2.0 Hz, 1H), 5.70 (s, 2H); 13 C NMR (125 MHz, DMSO- d 6 ) δ 168.3, 157.3, 156.7, 148.0, 139.3, 130.8, 130.6, 125.3, 124.2, 124.0, 123.3, 121.4, 121.2, 121.1, 1 20.5, 119.3, 118.5, 118.3, 56.6 .
25) 2-피리딘-3-일메틸-2H-인다졸-6-카르복실산[2-Pyridin-3-ylmethyl-2H-indazole-6-carboxylic acid; 화합물 75]25) 2-Pyridin-3-ylmethyl-2 H -indazole-6-carboxylic acid [2-Pyridin-3-ylmethyl-2 H -indazole-6-carboxylic acid; Compound 75]
흰색 고체; 수율 80%, 1H NMR (500 MHz, DMSO-d 6) δ 12.90 (s, 1H), 9.02 (s, 1H), 8.88 (d, J = 5.4 Hz, 1H), 8.77 (s, 1H), 8.46 (d, J = 8.1 Hz, 1H), 8.25 (s, 1H), 8.03 - 7.98 (m, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.57 (dd, J = 8.8, 1.2 Hz, 1H), 6.00 (s, 2H); 13C NMR (125 MHz, DMSO-d 6) δ 168.1, 148.3, 145.1, 142.6, 142.3, 136.4, 129.0, 127.5, 126.2, 123.9, 121.7, 121.4, 120.5, 53.3.white solid; Yield 80%, 1H NMR (500 MHz, DMSO- d 6 ) δ 12.90 (s, 1H), 9.02 (s, 1H), 8.88 (d, J = 5.4 Hz, 1H), 8.77 (s, 1H), 8.46 (d, J = 8.1 Hz, 1H), 8.25 (s, 1H), 8.03 - 7.98 (m, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.57 (dd, J = 8.8, 1.2 Hz) , 1H), 6.00 (s, 2H); 13 C NMR (125 MHz, DMSO- d 6 ) δ 168.1, 148.3, 145.1, 142.6, 142.3, 136.4, 129.0, 127.5, 126.2, 123.9, 121.7, 121.4, 120.5, 53.3.
3. 3. N2N2 치환된 2 substituted 2 HH -인다졸-6-카르복실산 하이드록시아마이드 유도체 합성(화합물 50 - 화합물 73, 화합물 76)-Synthesis of indazole-6-carboxylic acid hydroxyamide derivatives (Compound 50 - Compound 73, Compound 76)
카르복실산 유도체(화합물 26-49 및 화합물 75; 1 mmol), 하이드록시아민 염산염(3 mmol), BOP(benzotriazol-l-yl-oxy-tris-(dimethylamino)phosphonium hexa-fluorophosphate; 1.7 mmol) 및 DIPEA(diisopropylethylamine; 3 mmol)의 혼합물을 DMSO(5-10 ml)에 첨가하고 실온에서 6-8 시간 동안 교반하였다. 반응혼합물을 물로 희석한 후 에틸아세테이트로 추출하였다. 용출액으로 클로로포름:메탄올(90:10)을 이용한 컬럼 크로마토그래피에 의해 생성물을 정제하였다.Carboxylic acid derivatives (Compound 26-49 and Compound 75; 1 mmol), hydroxyamine hydrochloride (3 mmol), BOP (benzotriazol-l-yl-oxy-tris-(dimethylamino)phosphonium hexa-fluorophosphate; 1.7 mmol) and A mixture of diisopropylethylamine (DIPEA; 3 mmol) was added to DMSO (5-10 ml) and stirred at room temperature for 6-8 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The product was purified by column chromatography using chloroform:methanol (90:10) as an eluent.
1) SPA3602[2-벤질-21) SPA3602[2-benzyl-2 HH -인다졸-6-카르복실산 하이드록시아마이드(2-Benzyl-2-Indazole-6-carboxylic acid hydroxyamide (2-Benzyl-2 HH -indazole-6-carboxylic acid hydroxyamide; 화합물 50)]-indazole-6-carboxylic acid hydroxyamide; Compound 50)]
흰색 고체; 수율 68%, 1H NMR (500 MHz, DMSO-d 6) δ 11.22 (s, 1H), 9.02 (s, 1H), 8.56 (s, 1H), 8.02 (s, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.41 (d, J = 8.7 Hz, 1H), 7.39 - 7.29 (m, 5H); 13C NMR (125 MHz, DMSO-d 6) δ 165.3, 147.9, 137.2, 130.6, 129.0, 128.4, 124.8, 123.1, 121.3, 120.0, 116.8, 56.9; MS (in mouse) 79.3, (in human) 97.6.white solid; Yield 68%, 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.22 (s, 1H), 9.02 (s, 1H), 8.56 (s, 1H), 8.02 (s, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.41 (d, J = 8.7 Hz, 1H), 7.39 - 7.29 (m, 5H); 13 C NMR (125 MHz, DMSO- d 6 ) δ 165.3, 147.9, 137.2, 130.6, 129.0, 128.4, 124.8, 123.1, 121.3, 120.0, 116.8, 56.9; MS (in mouse) 79.3, (in human) 97.6.
2) SPA3603[2-(4-메톡시벤질)-22) SPA3603[2-(4-methoxybenzyl)-2 HH -인다졸-6-카르복실산 하이드록시아마이드(2-(4-Methoxybenzyl)-2-Indazole-6-carboxylic acid hydroxyamide (2-(4-Methoxybenzyl)-2 HH -indazole-6-carboxylic acid hydroxyamide; 화합물 51)]-indazole-6-carboxylic acid hydroxyamide; Compound 51)]
흰색 고체; 수율 62%, 1H NMR (500 MHz, DMSO-d 6) δ 11.22 (s, 1H), 9.01 (s, 1H), 8.49 (s, 1H), 8.02 (s, 1H), 7.75 (d, J = 8.7 Hz, 1H), 7.40 (d, J = 8.7 Hz, 1H), 7.33 (d, J = 8.7 Hz, 2H), 6.92 (d, J = 8.7 Hz, 2H), 5.60 (s, 2H), 3.73 (s, 3H); 13C NMR (125 MHz, DMSO-d 6) δ 165.3, 159.5, 14738, 130.5, 130.0, 129.1, 124.4, 123.1, 121.2, 119.9, 11638, 114.4, 56.5, 55,5; MS (in mouse) 98.6, (in human) 76.7.white solid; Yield 62%, 1H NMR (500 MHz, DMSO- d 6 ) δ 11.22 (s, 1H), 9.01 (s, 1H), 8.49 (s, 1H), 8.02 (s, 1H), 7.75 (d, J = 8.7 Hz, 1H), 7.40 (d, J = 8.7 Hz, 1H), 7.33 (d, J = 8.7 Hz, 2H), 6.92 (d, J = 8.7 Hz, 2H), 5.60 (s, 2H), 3.73 (s, 3H); 13 C NMR (125 MHz, DMSO- d 6 ) δ 165.3, 159.5, 14738, 130.5, 130.0, 129.1, 124.4, 123.1, 121.2, 119.9, 11638, 114.4, 56.5, 55,5; MS (in mouse) 98.6, (in human) 76.7.
3) SPA3606[2-(4-메틸벤질)-23) SPA3606[2-(4-methylbenzyl)-2 HH -인다졸-6-카르복실산 하이드록시아마이드(2-(4-Methylbenzyl)-2-Indazole-6-carboxylic acid hydroxyamide (2-(4-Methylbenzyl)-2 HH -indazole-6-carboxylic acid hydroxyamide; 화합물 52)]-indazole-6-carboxylic acid hydroxyamide; Compound 52)]
흰색 고체; 수율 75%, 1H NMR (500 MHz, DMSO-d 6) δ 11.22 (s, 1H), 9.01 (s, 1H), 8.51 (s, 1H), 8.02 (s, 1H), 7.76 (d, J = 8.7 Hz, 1H), 7.40 (d, J = 8.7 Hz, 1H), 7.24 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 5.63 (s, 2H), 2.28 (s, 3H); 13C NMR (125 MHz, DMSO-d 6) δ 165.2, 147.8, 137.7, 137.7, 134.1, 130.4, 129.6, 128.4, 124.7, 123.0, 121.2, 119.9, 116.7, 56.7, 21.1.white solid; Yield 75%, 1H NMR (500 MHz, DMSO- d 6 ) δ 11.22 (s, 1H), 9.01 (s, 1H), 8.51 (s, 1H), 8.02 (s, 1H), 7.76 (d, J = 8.7 Hz, 1H), 7.40 (d, J = 8.7 Hz, 1H), 7.24 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 5.63 (s, 2H), 2.28 (s, 3H); 13 C NMR (125 MHz, DMSO- d 6 ) δ 165.2, 147.8, 137.7, 137.7, 134.1, 130.4, 129.6, 128.4, 124.7, 123.0, 121.2, 119.9, 116.7, 56.7, 21 .1.
4) SPA3608[2-(4-플루오로벤질)-24) SPA3608[2-(4-fluorobenzyl)-2 HH -인다졸-6-카르복실산 하이드록시아마이드(2-(4-Fluorobenzyl)-2-Indazole-6-carboxylic acid hydroxyamide (2-(4-Fluorobenzyl)-2 HH -indazole-6-carboxylic acid hydroxyamide; 화합물 53)]-indazole-6-carboxylic acid hydroxyamide; Compound 53)]
흰색 고체; 수율 66%, 1H NMR (500 MHz, DMSO-d 6) δ 11.23 (s, 1H), 9.02 (s, 1H), 8.56 (s, 1H), 8.02 (s, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.39 - 7.43 (m, 3H), 7.20 (t, J = 8.8 Hz, 2H), 5.68 (s, 2H); 13C NMR (125 MHz, DMSO-d 6) δ 165.2, 163.2, 161.3, 147.9, 133.4, 130.7, 130.6, 124.8, 121.3, 120.0, 116.8, 115.8, 56.1; MS (in mouse) 71.3, (in human) 85.9.white solid; Yield 66%, 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.23 (s, 1H), 9.02 (s, 1H), 8.56 (s, 1H), 8.02 (s, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.39 - 7.43 (m, 3H), 7.20 (t, J = 8.8 Hz, 2H), 5.68 (s, 2H); 13 C NMR (125 MHz, DMSO- d 6 ) δ 165.2, 163.2, 161.3, 147.9, 133.4, 130.7, 130.6, 124.8, 121.3, 120.0, 116.8, 115.8, 56.1; MS (in mouse) 71.3, (in human) 85.9.
5) SPA3610[2-(4-클로로벤질)-25) SPA3610[2-(4-chlorobenzyl)-2 HH -인다졸-6-카르복실산 하이드록시아마이드(2-(4-Chlorobenzyl)-2-Indazole-6-carboxylic acid hydroxyamide (2-(4-Chlorobenzyl)-2 HH -indazole-6-carboxylic acid hydroxyamide; 화합물 54)]-indazole-6-carboxylic acid hydroxyamide; Compound 54)]
흰색 고체; 수율 77%; 1H NMR (500 MHz, DMSO-d 6) δ 11.28 (s, 1H), 9.07 (s, 1H), 8.61 (s, 1H), 8.07 (s, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.45 - 7.49 (m, 3H), 7.40 (d, J = 8.4 Hz, 2H), 5.74 (s, 2H); 13C NMR (125 MHz, DMSO-d 6) δ 165.2, 148.0, 136.1, 133.1, 130.7, 130.3, 129.0, 125.0, 123.1, 121.1, 120.1, 116.8, 56.1; MS (in mouse) 40.8, (in human) 49.3.white solid; Yield 77%; 1H NMR (500 MHz, DMSO- d6 ) δ 11.28 (s, 1H) , 9.07 (s, 1H), 8.61 (s, 1H), 8.07 (s, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.45 - 7.49 (m, 3H), 7.40 (d, J = 8.4 Hz, 2H), 5.74 (s, 2H); 13 C NMR (125 MHz, DMSO- d 6 ) δ 165.2, 148.0, 136.1, 133.1, 130.7, 130.3, 129.0, 125.0, 123.1, 121.1, 120.1, 116.8, 56.1; MS (in mouse) 40.8, (in human) 49.3.
6) SPA3612[2-(4-브로모벤질)-26) SPA3612[2-(4-bromobenzyl)-2 HH -인다졸-6-카르복실산 하이드록시아마이드(2-(4-Bromobenzyl)-2-Indazole-6-carboxylic acid hydroxyamide (2-(4-Bromobenzyl)-2 HH -indazole-6-carboxylic acid hydroxyamide; 화합물 55)]-indazole-6-carboxylic acid hydroxyamide; Compound 55)]
흰색 고체; 수율 59%, 1H NMR (500 MHz, DMSO-d 6) δ 11.23 (s, 1H), 9.02 (s, 1H), 8.56 (s, 1H), 8.02 (s, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.7 Hz, 1H), 7.28 (d, J = 8.4 Hz, 2H), 5.68 (s, 2H); 13C NMR (125 MHz, DMSO-d 6) δ 165.2, 148.0, 136.6, 132.0, 130.7, 130.6, 125.1 ,123.0, 121.6, 121.6, 120.1, 116.8, 56.1.white solid; Yield 59%, 1H NMR (500 MHz, DMSO- d 6 ) δ 11.23 (s, 1H), 9.02 (s, 1H), 8.56 (s, 1H), 8.02 (s, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.7 Hz, 1H), 7.28 (d, J = 8.4 Hz, 2H), 5.68 (s, 2H); 13 C NMR (125 MHz, DMSO- d 6 ) δ 165.2, 148.0, 136.6, 132.0, 130.7, 130.6, 125.1, 123.0, 121.6, 121.6, 120.1, 116.8, 56.1.
7) SPA3614[2-(3-트리플루오로메톡시벤질)-27) SPA3614[2-(3-trifluoromethoxybenzyl)-2 H-H- 인다졸-6-카르복실산 하이드록시아마이드(2-(3-Trifluoromethoxybenzyl)-2Indazole-6-carboxylic acid hydroxyamide (2-(3-Trifluoromethoxybenzyl)-2 H-H- indazole-6-carboxylic acid hydroxyamide; 화합물 56)]indazole-6-carboxylic acid hydroxyamide; Compound 56)]
흰색 고체; 수율 74%, 1H NMR (500 MHz, DMSO-d 6) δ 11.23 (s, 1H), 9.03 (s, 1H), 8.61 (s, 1H), 8.03 (s, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.50 (t, J = 7.9 Hz, 1H), 7.42 (d, J = 8.7 Hz, 1H), 7.37 (s, 1H), 7.31 - 7.35 (m, 2H), 5.77 (s, 2H); 13C NMR (125 MHz, DMSO-d 6) δ 165.3, 148.7, 148.0, 139.9, 131.1, 130.7, 127.4, 125.2, 123.0, 122.0 121.4, 120.8, 120.1, 119.4, 116.8, 56.1.white solid; Yield 74%, 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.23 (s, 1H), 9.03 (s, 1H), 8.61 (s, 1H), 8.03 (s, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.50 (t, J = 7.9 Hz, 1H), 7.42 (d, J = 8.7 Hz, 1H), 7.37 (s, 1H), 7.31 - 7.35 (m, 2H), 5.77 (s , 2H); 13 C NMR (125 MHz, DMSO- d 6 ) δ 165.3, 148.7, 148.0, 139.9, 131.1, 130.7, 127.4, 125.2, 123.0, 122.0 121.4, 120.8, 120.1, 119.4, 11 6.8, 56.1.
8) SPA3616[2-(4-트리플루오로메톡시벤질)-28) SPA3616[2-(4-trifluoromethoxybenzyl)-2 HH -인다졸-6-카르복실산 하이드록시아마이드(2-(4-Trifluoromethoxybenzyl)-2-Indazole-6-carboxylic acid hydroxyamide (2-(4-Trifluoromethoxybenzyl)-2 HH -indazole-6-carboxylic acid hydroxyamide; 화합물 57)]-indazole-6-carboxylic acid hydroxyamide; Compound 57)]
흰색 고체; 수율 71%, 1H NMR (500 MHz, DMSO-d 6) δ 11.22 (s, 1H), 9.02 (s, 1H), 8.59 (s, 1H), 8.03 (s, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.46 (d, J = 8.7 Hz, 2H), 7.41 (d, J = 8.7 Hz, 1H), 7.37 (d, J = 8.7 Hz, 2H), 5.74 (s, 2H); 13C NMR (125 MHz, DMSO-d 6) δ 165.2, 148.4, 148.0, 136.7, 130.7, 125.1, 123.1, 121.7, 121.3, 120.8, 120.1, 117.0, 116.8, 56.1.white solid; Yield 71%, 1H NMR (500 MHz, DMSO- d 6 ) δ 11.22 (s, 1H), 9.02 (s, 1H), 8.59 (s, 1H), 8.03 (s, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.46 (d, J = 8.7 Hz, 2H), 7.41 (d, J = 8.7 Hz, 1H), 7.37 (d, J = 8.7 Hz, 2H), 5.74 (s, 2H); 13 C NMR (125 MHz, DMSO- d 6 ) δ 165.2, 148.4, 148.0, 136.7, 130.7, 125.1, 123.1, 121.7, 121.3, 120.8, 120.1, 117.0, 116.8, 56.1.
9) SPA3618[2-나프탈렌-2-일메틸-29) SPA3618 [2-naphthalen-2-ylmethyl-2 HH -인다졸-6-카르복실산 하이드록시아마이드(2-Naphthalen-2-ylmethyl-2-Indazole-6-carboxylic acid hydroxyamide (2-Naphthalen-2-ylmethyl-2 HH -indazole-6-carboxylic acid hydroxyamide; 화합물 58)]-indazole-6-carboxylic acid hydroxyamide; Compound 58)]
흰색 고체; 수율 71%, 1H NMR (500 MHz, DMSO-d 6) δ 11.23 (s, 1H), 9.02 (s, 1H), 8.62 (s, 1H), 8.03 (s, 1H), 7.89 - 7.93 (m, 4H), 7.78 (d, J = 8.7 Hz, 1H), 7.57 - 7.50 (m, 2H), 7.48 (d, J = 7.7 Hz, 1H), 7.42 (d, J = 8.7 Hz, 1H), 5.86 (s, 2H); 13C NMR (125 MHz, DMSO-d 6) δ 165.3, 147.9, 134.7, 133.2, 132.9, 130.6, 128.7, 128.2, 127.3, 126.9, 126.3, 125.0, 123.1, 121.3, 120.0, 116.8, 57.1.white solid; Yield 71%, 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.23 (s, 1H), 9.02 (s, 1H), 8.62 (s, 1H), 8.03 (s, 1H), 7.89 - 7.93 (m , 4H), 7.78 (d, J = 8.7 Hz, 1H), 7.57 - 7.50 (m, 2H), 7.48 (d, J = 7.7 Hz, 1H), 7.42 (d, J = 8.7 Hz, 1H), 5.86 (s, 2H); 13 C NMR (125 MHz, DMSO- d 6 ) δ 165.3, 147.9, 134.7, 133.2, 132.9, 130.6, 128.7, 128.2, 127.3, 126.9, 126.3, 125.0, 123.1, 121.3, 1 20.0, 116.8, 57.1.
10) SPA3620[2-페네틸-210) SPA3620[2-phenethyl-2 H-H- 인다졸-6-카르복실산 하이드록시아마이드(2-Phenethyl-2Indazole-6-carboxylic acid hydroxyamide (2-Phenethyl-2 H-H- indazole-6-carboxylic acid hydroxyamide; 화합물 59)]indazole-6-carboxylic acid hydroxyamide; Compound 59)]
흰색 고체; 수율 77%, 1H NMR (500 MHz, DMSO-d 6) δ 11.25 (s, 1H), 9.04 (s, 1H), 8.32 (s, 1H), 8.04 (s, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.38 (d, J = 8.6 Hz, 1H), 7.17-7.27 (m, 5H), 4.72 (t, J = 6.9 Hz, 2H), 3.28 (t, J = 6.9 Hz, 2H); 13C NMR (125 MHz, DMSO-d 6) δ 165.3, 147.6, 138.4, 129.0, 128.8, 126.9, 124.7, 122.7, 121.2, 119.8, 116.7, 54.5, 36.4.white solid; Yield 77%, 1H NMR (500 MHz, DMSO- d 6 ) δ 11.25 (s, 1H), 9.04 (s, 1H), 8.32 (s, 1H), 8.04 (s, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.38 (d, J = 8.6 Hz, 1H), 7.17-7.27 (m, 5H), 4.72 (t, J = 6.9 Hz, 2H), 3.28 (t, J = 6.9 Hz, 2H) ); 13 C NMR (125 MHz, DMSO- d 6 ) δ 165.3, 147.6, 138.4, 129.0, 128.8, 126.9, 124.7, 122.7, 121.2, 119.8, 116.7, 54.5, 36.4.
11) SPA3622[2-(2-4-메톡시페닐에틸)-211) SPA3622[2-(2-4-methoxyphenylethyl)-2 HH -인다졸-6-카르복실산 하이드록시아마이드(2-(2-4-Methoxyphenylethyl)-2-Indazole-6-carboxylic acid hydroxyamide (2-(2-4-Methoxyphenylethyl)-2 HH -indazole-6-carboxylic acid hydroxyamide; 화합물 60)]-indazole-6-carboxylic acid hydroxyamide; Compound 60)]
흰색 고체; 수율 66%, 1H NMR (500 MHz, DMSO-d 6) δ 11.25 (s, 1H), 9.04 (s, 1H), 8.31 (s, 1H), 8.04 (s, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.38 (d, J = 8.7 Hz, 1H), 7.08 (d, J = 8.6 Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 4.66 (t, J = 7.2 Hz, 2H), 3.69 (s, 3H), 3.20 (t, J = 7.2 Hz, 2H); 13C NMR (125 MHz, DMSO-d 6) δ 165.3, 158.3, 147.6, 130.4, 130.2, 130.1, 124.7, 122.7, 121.2, 119.7, 116.7, 114.2, 55.4, 54.8, 35.6.white solid; Yield 66%, 1H NMR (500 MHz, DMSO- d 6 ) δ 11.25 (s, 1H), 9.04 (s, 1H), 8.31 (s, 1H), 8.04 (s, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.38 (d, J = 8.7 Hz, 1H), 7.08 (d, J = 8.6 Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 4.66 (t, J = 7.2 Hz, 2H), 3.69 (s, 3H), 3.20 (t, J = 7.2 Hz, 2H); 13 C NMR (125 MHz, DMSO- d 6 ) δ 165.3, 158.3, 147.6, 130.4, 130.2, 130.1, 124.7, 122.7, 121.2, 119.7, 116.7, 114.2, 55.4, 54.8, 35. 6.
12) SPA3624[2-(3,5-다이플로오로벤질)-212) SPA3624[2-(3,5-difluorobenzyl)-2 HH -인다졸-6-카르복실산 하이드록시아마이드(2-(3,5-Difluorobenzyl)-2-Indazole-6-carboxylic acid hydroxyamide (2-(3,5-Difluorobenzyl)-2 HH -indazole-6-carboxylic acid hydroxyamide; 화합물 61)]-indazole-6-carboxylic acid hydroxyamide; Compound 61)]
흰색 고체; 수율 79%, 1H NMR (500 MHz, DMSO-d 6) δ 11.24 (s, 1H), 9.03 (s, 1H), 8.60 (s, 1H), 8.04 (s, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.42 (d, J = 8.7 Hz, 1H), 7.21 (tt, J = 8.9 Hz, 2.3Hz, 1H), 7.05 (d, J = 6.2 Hz, 2H), 5.73 (s, 2H); 13C NMR (125 MHz, DMSO-d 6) δ 165.2, 163.7, 161.8, 148.1, 141.4, 130.8, 125.4, 123.0, 121.4, 120.2, 116.8, 111.5, 103.9, 55.8.white solid; Yield 79%, 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.24 (s, 1H), 9.03 (s, 1H), 8.60 (s, 1H), 8.04 (s, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.42 (d, J = 8.7 Hz, 1H), 7.21 (tt, J = 8.9 Hz, 2.3Hz, 1H), 7.05 (d, J = 6.2 Hz, 2H), 5.73 (s, 2H); 13 C NMR (125 MHz, DMSO- d 6 ) δ 165.2, 163.7, 161.8, 148.1, 141.4, 130.8, 125.4, 123.0, 121.4, 120.2, 116.8, 111.5, 103.9, 55.8.
13) SPA3626[2-(4-다이플루오로메톡시벤질)-213) SPA3626[2-(4-difluoromethoxybenzyl)-2 HH -인다졸-6-카르복실산 하이드록시아마이드(2-(4-Difluoromethoxybenzyl)-2-Indazole-6-carboxylic acid hydroxyamide (2-(4-Difluoromethoxybenzyl)-2 HH -indazole-6-carboxylic acid hydroxyamide; 화합물 62)]-indazole-6-carboxylic acid hydroxyamide; Compound 62)]
흰색 고체; 수율 62%, 1H NMR (500 MHz, DMSO-d 6) δ 11.22 (s, 1H), 9.02 (s, 1H), 8.56 (s, 1H), 8.02 (s, 1H), 7.76 (d, J = 8.7, 1H), 7.39 - 7.43 (m, 3H), 7.21 (t, J = 74.0, 1H), 7.17 (d, J = 8.8, 2H), 7.26 - 6.99 (m, 3H), 5.69 (s, 2H); 13C NMR (125 MHz, DMSO-d 6) δ 165.2, 151.0, 147.9, 134.1, 130.6, 130.2, 124.9, 123.1, 121.3, 120.0, 119.4, 118.8, 116.8, 56.2.white solid; Yield 62%, 1H NMR (500 MHz, DMSO- d 6 ) δ 11.22 (s, 1H), 9.02 (s, 1H), 8.56 (s, 1H), 8.02 (s, 1H), 7.76 (d, J = 8.7, 1H), 7.39 - 7.43 (m, 3H), 7.21 (t, J = 74.0, 1H), 7.17 (d, J = 8.8, 2H), 7.26 - 6.99 (m, 3H), 5.69 (s, 2H); 13 C NMR (125 MHz, DMSO- d 6 ) δ 165.2, 151.0, 147.9, 134.1, 130.6, 130.2, 124.9, 123.1, 121.3, 120.0, 119.4, 118.8, 116.8, 56.2.
14) SPA3628[2-바이페닐-4-일메틸-214) SPA3628 [2-biphenyl-4-ylmethyl-2 HH -인다졸-6-카르복실산 하이드록시아마이드(2-Biphenyl-4-ylmethyl-2-Indazole-6-carboxylic acid hydroxyamide (2-Biphenyl-4-ylmethyl-2 HH -indazole-6-carboxylic acid hydroxyamide; 화합물 63)]-indazole-6-carboxylic acid hydroxyamide; Compound 63)]
흰색 고체; 수율 78%, 1H NMR (500 MHz, DMSO-d 6) δ 11.23 (s, 1H), 9.02 (s, 1H), 8.60 (s, 1H), 8.04 (s, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.63 - 7.67 (m, 4H), 7.51 - 7.40 (m, 5H), 7.37 (t, J = 7.3 Hz, 1H), 5.74 (s, 2H); 13C NMR (125 MHz, DMSO-d 6) δ 165.2, 147.9, 140.3, 140.1, 136.4, 130.6, 129.4, 129.0, 128.0, 127.3, 127.1, 125.0, 123.1, 121.3, 120.0, 116.8, 56.6.white solid; Yield 78%, 1H NMR (500 MHz, DMSO- d 6 ) δ 11.23 (s, 1H), 9.02 (s, 1H), 8.60 (s, 1H), 8.04 (s, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.63 - 7.67 (m, 4H), 7.51 - 7.40 (m, 5H), 7.37 (t, J = 7.3 Hz, 1H), 5.74 (s, 2H); 13 C NMR (125 MHz, DMSO- d 6 ) δ 165.2, 147.9, 140.3, 140.1, 136.4, 130.6, 129.4, 129.0, 128.0, 127.3, 127.1, 125.0, 123.1, 121.3, 1 20.0, 116.8, 56.6.
15) SPA3630[2-(4-아이소프로필벤질)-215) SPA3630[2-(4-isopropylbenzyl)-2 HH -인다졸-6-카르복실산 하이드록시아마이드(2-(4-Isopropylbenzyl)-2-Indazole-6-carboxylic acid hydroxyamide (2-(4-Isopropylbenzyl)-2 HH -indazole-6-carboxylic acid hydroxyamide; 화합물 64)]-indazole-6-carboxylic acid hydroxyamide; Compound 64)]
연노란색 고체; 수율 77%, 1H NMR (500 MHz, DMSO-d 6) δ 11.22 (s, 1H), 9.01 (s, 1H), 8.54 (s, 1H), 8.02 (s, 1H), 7.76 (d, J = 8.7 Hz, 1H), 7.40 (d, J = 8.7 Hz, 1H), 7.28 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 5.63 (s, 2H), 2.91 - 2.84 (m, 1H), 1.14 (dd, J = 33.7, 6.8 Hz, 6H).Light yellow solid; Yield 77%, 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.22 (s, 1H), 9.01 (s, 1H), 8.54 (s, 1H), 8.02 (s, 1H), 7.76 (d, J = 8.7 Hz, 1H), 7.40 (d, J = 8.7 Hz, 1H), 7.28 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 5.63 (s, 2H), 2.91 - 2.84 (m, 1H), 1.14 (dd, J = 33.7, 6.8 Hz, 6H).
16) SPA3632[2-(2-4-플루오로페닐에틸)-216) SPA3632[2-(2-4-fluorophenylethyl)-2 HH -인다졸-6-카르복실산 하이드록시아마이드(2-(2-4-Fluorophenylethyl)-2-Indazole-6-carboxylic acid hydroxyamide (2-(2-4-Fluorophenylethyl)-2 HH -indazole-6-carboxylic acid hydroxyamide; 화합물 65)]-indazole-6-carboxylic acid hydroxyamide; Compound 65)]
적색 고체; 수율 19%, 1H NMR (500 MHz, DMSO-d 6) δ 11.23 (s, 1H), 9.01 (s, 1H), 8.31 (s, 1H), 8.03 (s, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.38 (d, J = 8.7 Hz, 1H), 7.20 (dd, J = 8.4, 5.7 Hz, 2H), 7.07 (t, J = 8.4 Hz, 2H), 4.70 (t, J = 7.2 Hz, 2H), 3.27 (t, J = 7.2 Hz, 2H).red solid; Yield 19%, 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.23 (s, 1H), 9.01 (s, 1H), 8.31 (s, 1H), 8.03 (s, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.38 (d, J = 8.7 Hz, 1H), 7.20 (dd, J = 8.4, 5.7 Hz, 2H), 7.07 (t, J = 8.4 Hz, 2H), 4.70 (t, J) = 7.2 Hz, 2H), 3.27 (t, J = 7.2 Hz, 2H).
17) SPA3634[2-(3-플루오로벤질)-217) SPA3634[2-(3-fluorobenzyl)-2 HH -인다졸-6-카르복실산 하이드록시아마이드(2-(3-Fluorobenzyl)-2-Indazole-6-carboxylic acid hydroxyamide (2-(3-Fluorobenzyl)-2 HH -indazole-6-carboxylic acid hydroxyamide; 화합물 66)]-indazole-6-carboxylic acid hydroxyamide; Compound 66)]
흰색 고체; 수율 67%, 1H NMR (500 MHz, DMSO-d 6) δ 11.24 (s, 1H), 9.05 (s, 1H), 8.58 (s, 1H), 8.03 (s, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.47 - 7.33 (m, 2H), 7.21 - 7.09 (m, 3H), 5.71 (s, 2H); 13C NMR (125 MHz, DMSO-d 6) δ 165.3, 161.6, 148.0, 139.9, 131.1, 130.7, 125.2, 124.5, 123.1, 121.4, 120.1, 116.8, 115.3, 115.1, 56.3.white solid; Yield 67%, 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.24 (s, 1H), 9.05 (s, 1H), 8.58 (s, 1H), 8.03 (s, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.47 - 7.33 (m, 2H), 7.21 - 7.09 (m, 3H), 5.71 (s, 2H); 13 C NMR (125 MHz, DMSO- d 6 ) δ 165.3, 161.6, 148.0, 139.9, 131.1, 130.7, 125.2, 124.5, 123.1, 121.4, 120.1, 116.8, 115.3, 115.1, 5 6.3.
18) SPA3636[2-(3-클로로벤질)-218) SPA3636[2-(3-chlorobenzyl)-2 HH -인다졸-6-카르복실산 하이드록시아마이드(2-(3-Chlorobenzyl)-2-Indazole-6-carboxylic acid hydroxyamide (2-(3-Chlorobenzyl)-2 HH -indazole-6-carboxylic acid hydroxyamide; 화합물 67)]-indazole-6-carboxylic acid hydroxyamide; Compound 67)]
연주황색 고체; 수율 90%, 1H NMR (500 MHz, DMSO-d 6) δ 11.22 (s, 1H), 9.01 (s, 1H), 8.59 (s, 1H), 8.02 (s, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.52 - 7.32 (m, 4H), 7.28 (s, 1H), 5.70 (s, 2H); 13C NMR (125 MHz, DMSO-d 6) δ 148.0, 139.6, 133.6, 131.0, 130.8, 128.4, 128.2, 127.1, 125.2, 123.1, 121.4, 120.1, 116.8, 108.3, 56.2.Light yellow solid; Yield 90%, 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.22 (s, 1H), 9.01 (s, 1H), 8.59 (s, 1H), 8.02 (s, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.52 - 7.32 (m, 4H), 7.28 (s, 1H), 5.70 (s, 2H); 13 C NMR (125 MHz, DMSO- d 6 ) δ 148.0, 139.6, 133.6, 131.0, 130.8, 128.4, 128.2, 127.1, 125.2, 123.1, 121.4, 120.1, 116.8, 108.3, 5 6.2.
19) SPA3638[2-(3-트리플루오로메틸벤질)-219) SPA3638[2-(3-trifluoromethylbenzyl)-2 HH -인다졸-6-카르복실산 하이드록시아마이드(2-(3-Trifluoromethylbenzyl)-2-Indazole-6-carboxylic acid hydroxyamide (2-(3-Trifluoromethylbenzyl)-2 HH -indazole-6-carboxylic acid hydroxyamide; 화합물 68)]-indazole-6-carboxylic acid hydroxyamide; Compound 68)]
흰색 고체; 수율 63%, 1H NMR (500 MHz, DMSO-d 6) δ 11.23 (s, 1H), 9.03 (s, 1H), 8.62 (s, 1H), 8.03 (s, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.75 (s, 1H), 7.72 - 7.65 (m, 1H), 7.60 (d, J = 5.2 Hz, 2H), 7.42 (d, J = 8.8 Hz, 1H), 5.81 (s, 2H); 13C NMR (125 MHz, DMSO-d 6) δ 165.3, 148.1, 138.6, 132.6, 130.8, 130.3, 129.7, 125.3, 125.2, 125.0, 124.5, 123.1, 121.4, 120.2, 116.8, 56.2.white solid; Yield 63%, 1H NMR (500 MHz, DMSO- d 6 ) δ 11.23 (s, 1H), 9.03 (s, 1H), 8.62 (s, 1H), 8.03 (s, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.75 (s, 1H), 7.72 - 7.65 (m, 1H), 7.60 (d, J = 5.2 Hz, 2H), 7.42 (d, J = 8.8 Hz, 1H), 5.81 (s) , 2H); 13 C NMR (125 MHz, DMSO- d 6 ) δ 165.3, 148.1, 138.6, 132.6, 130.8, 130.3, 129.7, 125.3, 125.2, 125.0, 124.5, 123.1, 121.4, 120.2, 1 16.8, 56.2.
20) SPA3640[2-(4-트리플루오로메틸벤질)-220) SPA3640 [2-(4-trifluoromethylbenzyl)-2 HH -인다졸-6-카르복실산 하이드록시아마이드(2-(4-Trifluoromethylbenzyl)-2-Indazole-6-carboxylic acid hydroxyamide (2-(4-Trifluoromethylbenzyl)-2 HH -indazole-6-carboxylic acid hydroxyamide; 화합물 69)]-indazole-6-carboxylic acid hydroxyamide; Compound 69)]
흰색 고체; 수율 62%, 1H NMR (500 MHz, DMSO-d 6) δ 11.23 (s, 1H), 9.02 (s, 1H), 8.61 (s, 1H), 8.02 (s, 1H), 7.83 - 7.76 (m, 1H), 7.73 (d, J = 8.1 Hz, 2H), 7.49 (d, J = 8.1 Hz, 2H), 7.41 (dd, J = 8.7, 1.4 Hz, 1H), 5.81 (s, 2H); 13C NMR (125 MHz, DMSO-d 6) δ 165.3, 148.1, 141.9, 130.8, 129.0, 128.9, 126.0, 125.4, 124.6, 123.1, 121.4, 120.2, 116.8, 56.3.white solid; Yield 62%, 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.23 (s, 1H), 9.02 (s, 1H), 8.61 (s, 1H), 8.02 (s, 1H), 7.83 - 7.76 (m , 1H), 7.73 (d, J = 8.1 Hz, 2H), 7.49 (d, J = 8.1 Hz, 2H), 7.41 (dd, J = 8.7, 1.4 Hz, 1H), 5.81 (s, 2H); 13 C NMR (125 MHz, DMSO- d 6 ) δ 165.3, 148.1, 141.9, 130.8, 129.0, 128.9, 126.0, 125.4, 124.6, 123.1, 121.4, 120.2, 116.8, 56.3.
21) SPA3642[2-(3-메톡시벤질)-221) SPA3642[2-(3-methoxybenzyl)-2 HH -인다졸-6-카르복실산 하이드록시아마이드(2-(3-Methoxybenzyl)-2-Indazole-6-carboxylic acid hydroxyamide (2-(3-Methoxybenzyl)-2 HH -indazole-6-carboxylic acid hydroxyamide; 화합물 70)]-indazole-6-carboxylic acid hydroxyamide; Compound 70)]
흰색 고체; 수율 77%, 1H NMR (500 MHz, DMSO-d 6) δ 11.22 (s, 1H), 9.01 (s, 1H), 8.54 (s, 1H), 8.02 (s, 1H), 7.76 (d, J = 8.7 Hz, 1H), 7.43 - 7.35 (m, 1H), 7.26 (t, J = 7.9 Hz, 1H), 6.92 (s, 1H), 6.90 - 6.81 (m, 2H), 5.64 (s, 2H), 3.72 (s, 3H).white solid; Yield 77%, 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.22 (s, 1H), 9.01 (s, 1H), 8.54 (s, 1H), 8.02 (s, 1H), 7.76 (d, J = 8.7 Hz, 1H), 7.43 - 7.35 (m, 1H), 7.26 (t, J = 7.9 Hz, 1H), 6.92 (s, 1H), 6.90 - 6.81 (m, 2H), 5.64 (s, 2H) , 3.72 (s, 3H).
22) SPA3644[2-(3-벤질옥시벤질)-222) SPA3644[2-(3-benzyloxybenzyl)-2 HH -인다졸-6-카르복실산 하이드록시아마이드(2-(3-Benzyloxybenzyl)-2-Indazole-6-carboxylic acid hydroxyamide (2-(3-Benzyloxybenzyl)-2 HH -indazole-6-carboxylic acid hydroxyamide; 화합물 71)]-indazole-6-carboxylic acid hydroxyamide; Compound 71)]
흰색 고체; 수율 54%, 1H NMR (500 MHz, DMSO-d 6) δ 11.23 (s, 1H), 9.02 (s, 1H), 8.54 (s, 1H), 8.03 (s, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.46 - 7.23 (m, 7H), 7.00 (s, 1H), 6.97 (dd, J = 8.3, 2.6 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 5.65 (s, 2H), 5.07 (s, 2H); 13C NMR (125 MHz, DMSO-d 6) δ 165.3, 158.9, 147.9, 138.7, 137.3, 130.6, 130.2, 128.9, 128.3, 128.2, 125.0, 123.1, 121.3, 120.7, 120.0, 116.9, 115.1, 114.5, 69.7, 56.9.white solid; Yield 54%, 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.23 (s, 1H), 9.02 (s, 1H), 8.54 (s, 1H), 8.03 (s, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.46 - 7.23 (m, 7H), 7.00 (s, 1H), 6.97 (dd, J = 8.3, 2.6 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 5.65 (s, 2H), 5.07 (s, 2H); 13 C NMR (125 MHz, DMSO- d 6 ) δ 165.3, 158.9, 147.9, 138.7, 137.3, 130.6, 130.2, 128.9, 128.3, 128.2, 125.0, 123.1, 121.3, 120.7, 1 20.0, 116.9, 115.1, 114.5, 69.7 , 56.9.
23) SPA3646[2-(3,5-다이메톡시벤질)-223) SPA3646[2-(3,5-dimethoxybenzyl)-2 HH -인다졸-6-카르복실산 하이드록시아마이드(2-(3,5-Dimethoxybenzyl)-2-Indazole-6-carboxylic acid hydroxyamide (2-(3,5-Dimethoxybenzyl)-2 HH -indazole-6-carboxylic acid hydroxyamide; 화합물 72)]-indazole-6-carboxylic acid hydroxyamide; Compound 72)]
흰색 고체; 수율 40%, 1H NMR (500 MHz, DMSO-d 6) δ 11.21 (s, 1H), 9.01 (s, 1H), 8.53 (s, 1H), 8.02 (s, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 6.65 - 6.31 (m, 3H), 5.59 (s, 2H), 3.70 (s, 6H).white solid; Yield 40%, 1H NMR (500 MHz, DMSO- d 6 ) δ 11.21 (s, 1H), 9.01 (s, 1H), 8.53 (s, 1H), 8.02 (s, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 6.65 - 6.31 (m, 3H), 5.59 (s, 2H), 3.70 (s, 6H).
24) SPA3648[2-(3-페녹시벤질)-224) SPA3648[2-(3-phenoxybenzyl)-2 HH -인다졸-6-카르복실산 하이드록시아마이드(2-(3-Phenoxybenzyl)-2-Indazole-6-carboxylic acid hydroxyamide (2-(3-Phenoxybenzyl)-2 HH -indazole-6-carboxylic acid hydroxyamide; 화합물 73)]-indazole-6-carboxylic acid hydroxyamide; Compound 73)]
흰색 고체; 수율 67%, 1H NMR (500 MHz, DMSO-d 6) δ 8.55 (s, 1H), 8.01 (s, 1H), 7.76 (d, J = 8.7 Hz, 1H), 7.46 - 7.28 (m, 4H), 7.14 (t, J = 7.4 Hz, 1H), 7.06 (d, J = 7.7 Hz, 1H), 7.04 - 6.95 (m, 3H), 6.91 (dd, J = 8.2, 2.5 Hz, 1H), 5.68 (s, 2H); 13C NMR (125 MHz, DMSO-d 6) δ 157.3, 156.7, 147.9, 139.4, 130.7, 130.7, 130.6, 125.1, 124.1, 123.3, 123.1, 121.4, 120.1, 119.2, 118.4, 118.2, 116.8, 56.5.white solid; Yield 67%, 1H NMR (500 MHz, DMSO- d 6 ) δ 8.55 (s, 1H), 8.01 (s, 1H), 7.76 (d, J = 8.7 Hz, 1H), 7.46 - 7.28 (m, 4H) ), 7.14 (t, J = 7.4 Hz, 1H), 7.06 (d, J = 7.7 Hz, 1H), 7.04 - 6.95 (m, 3H), 6.91 (dd, J = 8.2, 2.5 Hz, 1H), 5.68 (s, 2H); 13 C NMR (125 MHz, DMSO- d 6 ) δ 157.3, 156.7, 147.9, 139.4, 130.7, 130.7, 130.6, 125.1, 124.1, 123.3, 123.1, 121.4, 120.1, 119.2, 1 18.4, 118.2, 116.8, 56.5.
25) SPA3650[2-피리딘-3-일메틸-225) SPA3650 [2-pyridin-3-ylmethyl-2 HH -인다졸-6-카르복실산 하이드록시아마이드(2-Pyridin-3-ylmethyl-2-Indazole-6-carboxylic acid hydroxyamide (2-Pyridin-3-ylmethyl-2 HH -indazole-6-carboxylic acid hydroxyamide; 화합물 76)]-indazole-6-carboxylic acid hydroxyamide; Compound 76)]
4. 2-플루오로-4-메틸-5-나이트로벤조산 화합물 합성(화합물 78)4. Synthesis of 2-fluoro-4-methyl-5-nitrobenzoic acid compound (Compound 78)
0℃에서 2-플루오로-4-메틸-5-나이트로 벤조산(1.95 mmol)을 H2SO4 (3 ml)에서 완전히 녹인 후 H2SO4(2.34 mmol)와 HNO3(2.92 mmol)의 혼합물을 천천히 적가한 후 3시간 동안 반응시켰다. 반응 완료 후 반응 혼합물을 얼음물에 넣고 침전물을 여과하고 건조하여 나이트로벤조산(화합물 78)을 얻었다. 1) 2-플루오로-4-메틸-5-나이트로벤조산[2-Fluoro-4-methyl-5-nitrobenzoic acid; 화합물 78]2-Fluoro-4-methyl-5-nitro benzoic acid (1.95 mmol) was completely dissolved in H 2 SO 4 (3 ml) at 0°C and then dissolved in H 2 SO 4 (2.34 mmol) and HNO 3 (2.92 mmol). The mixture was slowly added dropwise and reacted for 3 hours. After completion of the reaction, the reaction mixture was placed in ice water, and the precipitate was filtered and dried to obtain nitrobenzoic acid (Compound 78). 1) 2-Fluoro-4-methyl-5-nitrobenzoic acid [2-Fluoro-4-methyl-5-nitrobenzoic acid; Compound 78]
흰색 고체; 수율 93%, 1H NMR (500 MHz, DMSO-d 6) δ 13.76 (s, 1H), 8.45 (d, J = 6.8 Hz, 1H), 7.55 (d, J = 11.3 Hz, 1H), 2.59 (s, 3H). 13C NMR (125 MHz, DMSO-d 6) δ 163.6, 162.9, 145.1, 141.8, 129.4, 121.7, 118.4, 20.4.white solid; Yield 93% , 1H NMR (500 MHz, DMSO- d6 ) δ 13.76 (s, 1H), 8.45 (d, J = 6.8 Hz, 1H), 7.55 (d, J = 11.3 Hz, 1H), 2.59 ( s, 3H). 13 C NMR (125 MHz, DMSO- d 6 ) δ 163.6, 162.9, 145.1, 141.8, 129.4, 121.7, 118.4, 20.4.
5. 2-플루오로-4-메틸-5-나이트로벤조산 메틸 에스테르 화합물 합성(화합물 79)5. Synthesis of 2-fluoro-4-methyl-5-nitrobenzoic acid methyl ester compound (Compound 79)
2-플루오로-4-메틸-5-나이트로벤조산(화합물 78, 1.51 mmol)을 메탄올(3 ml)에서 용해시키고, H2SO4(7.53 mmol)을 천천히 적가하였다. 반응혼합물을 65℃에서 20시간 교반한 후, 반응 종결이 확인되면 반응혼합물을 얼음물에 넣고 침전물을 여과하고 건조하여 2-플루오로-4-메틸-5-나이트로벤조산 메틸 에스테르(화합물 79)를 얻었다.1) 2-플루오로-4-메틸-5-나이트로벤조산 메틸 에스테르[2-Fluoro-4-methyl-5-nitrobenzoic acid methyl ester; 화합물 79]2-Fluoro-4-methyl-5-nitrobenzoic acid (Compound 78, 1.51 mmol) was dissolved in methanol (3 ml), and H 2 SO 4 (7.53 mmol) was slowly added dropwise. The reaction mixture was stirred at 65°C for 20 hours, and when the reaction was complete, the reaction mixture was placed in ice water, the precipitate was filtered, and dried to produce 2-fluoro-4-methyl-5-nitrobenzoic acid methyl ester (Compound 79). Obtained. 1) 2-Fluoro-4-methyl-5-nitrobenzoic acid methyl ester [2-Fluoro-4-methyl-5-nitrobenzoic acid methyl ester; Compound 79]
흰색 고체; 수율 89%, 1H NMR (500 MHz, DMSO-d 6) δ 8.48 (d, J = 6.8 Hz, 1H), 7.61 (d, J = 11.4 Hz, 1H), 3.89 (s, 3H), 2.60 (s, 3H). 13C NMR (125 MHz, DMSO-d 6) δ 162.7, 162.7, 145.2, 142.4, 129.2, 121.9, 117.2, 53.3, 20.5.white solid; Yield 89%, 1H NMR (500 MHz, DMSO- d6 ) δ 8.48 (d, J = 6.8 Hz, 1H), 7.61 (d, J = 11.4 Hz, 1H), 3.89 (s, 3H), 2.60 ( s, 3H). 13 C NMR (125 MHz, DMSO- d 6 ) δ 162.7, 162.7, 145.2, 142.4, 129.2, 121.9, 117.2, 53.3, 20.5.
6. 5-아미노-2-플루오로-4-메틸벤조산 메틸 에스테르 화합물 합성(화합물 80)6. Synthesis of 5-amino-2-fluoro-4-methylbenzoic acid methyl ester compound (Compound 80)
N2 기체 하에서 에틸아세테이트(5 ml)에 2-플루오로-4-메틸-5-나이트로벤조산 메틸 에스테르(화합물 79)를 완전히 녹인 후 Pd/C을 첨가하였다. N2 기체에서 Ar 기체로 치환 후 실온(rt)에서 2시간 교반하고 반응 종료 확인되면 celite filtration으로 Pd/C를 제거하여 반응 종료를 하였다. 용출물로 헥산:에틸아세테이트(2:1)를 이용한 컬럼 크로마토그래피로 5-아미노-2-플루오로-4-메틸벤조산 메틸 에스테르(화합물 80)를 분리하였다. 2-Fluoro-4-methyl-5-nitrobenzoic acid methyl ester (Compound 79) was completely dissolved in ethyl acetate (5 ml) under N 2 gas, and then Pd/C was added. After replacing N 2 gas with Ar gas, the mixture was stirred at room temperature (rt) for 2 hours, and when the reaction was confirmed to be complete, Pd/C was removed through celite filtration to complete the reaction. 5-Amino-2-fluoro-4-methylbenzoic acid methyl ester (Compound 80) was separated by column chromatography using hexane:ethyl acetate (2:1) as an eluent.
1)　5-아미노-2-플루오로-4-메틸벤조산 메틸 에스테르[5-Amino-2-fluoro-4-methylbenzoic acid methyl ester; 화합물　８０]갈색 고체; 수율 91%, 1H NMR (500 MHz, DMSO-d 6) δ 7.10 (d, J = 6.6 Hz, 1H), 6.91 (d, J = 11.7 Hz, 1H), 4.99 (s, 2H), 3.79 (s, 3H), 2.09 (s, 3H). 13C NMR (125 MHz, DMSO-d 6) δ 165.0, 153.3, 143.6, 129.6, 118.2, 115.5, 115.3, 52.4, 18.0.1) 5-Amino-2-fluoro-4-methylbenzoic acid methyl ester [5-Amino-2-fluoro-4-methylbenzoic acid methyl ester; Compound 80] Brown solid; Yield 91%, 1H NMR (500 MHz, DMSO- d6 ) δ 7.10 (d, J = 6.6 Hz, 1H), 6.91 (d, J = 11.7 Hz, 1H), 4.99 (s, 2H), 3.79 ( s, 3H), 2.09 (s, 3H). 13 C NMR (125 MHz, DMSO- d 6 ) δ 165.0, 153.3, 143.6, 129.6, 118.2, 115.5, 115.3, 52.4, 18.0.
７. 5-플루오로-1７. 5-fluoro-1 HH -인다졸-6-카르복실산 메틸 에스테르　화합물 합성(화합물 81)-indazole-6-carboxylic acid methyl ester compound synthesis (compound 81)
클로로포름(5 ml)에서 5-아미노-2-플루오로-4-메틸벤조산 메틸 에스테르(화합물 80, 0.55 mmol), KOAc(0.28 mmol) 및 무수 아세트산(1.38 mmol)의 혼합물을 실온(rt)에서 1시간 동안 교반하였다. 그리고 아질산 아이소아밀(5.51 mmol)을 첨가하고 65℃에서 3시간 가열하여 반응시켰다. 반응 완료 후 반응 혼합물을 탄산수소 나트륨 포화용액으로 pH7을 맞추고 클로로포름으로 조산물(crude product)을 추출하였다. 용출물로 헥산:에틸아세테이트(1:1)를 이용한 컬럼크로마토그래피로 5-플루오로-1H-인다졸-6-카르복실산 메틸 에스테르(화합물 81)를 분리하였다. A mixture of 5-amino-2-fluoro-4-methylbenzoic acid methyl ester (Compound 80, 0.55 mmol), KOAc (0.28 mmol) and acetic anhydride (1.38 mmol) was reacted at room temperature (rt) at 1 mL. Stirred for an hour. Then, isoamyl nitrite (5.51 mmol) was added and heated at 65°C for 3 hours to react. After completion of the reaction, the pH of the reaction mixture was adjusted to 7 with saturated sodium bicarbonate solution, and the crude product was extracted with chloroform. 5-Fluoro-1H-indazole-6-carboxylic acid methyl ester (Compound 81) was separated by column chromatography using hexane:ethyl acetate (1:1) as an eluent.
1) 5-플루오로-1H-인다졸-6-카르복실산 메틸 에스테르[5-Fluoro-1H-indazole-6-carboxylic acid methyl ester; 화합물 81]1) 5-Fluoro-1 H -indazole-6-carboxylic acid methyl ester [5-Fluoro-1 H -indazole-6-carboxylic acid methyl ester; Compound 81]
노란색 고체; 수율 16%, 1H NMR (500 MHz, CDCl3) δ 10.30 (s, 1H), 8.17 (d, J = 5.5 Hz, 1H), 8.12 (s, 1H), 7.47 (d, J = 10.6 Hz, 1H), 3.98 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 165.2, 156.4, 136.0, 134.9, 125.6, 119.0, 113.9, 106.7, 52.7.yellow solid; Yield 16%, 1H NMR (500 MHz, CDCl 3 ) δ 10.30 (s, 1H), 8.17 (d, J = 5.5 Hz, 1H), 8.12 (s, 1H), 7.47 (d, J = 10.6 Hz, 1H), 3.98 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 165.2, 156.4, 136.0, 134.9, 125.6, 119.0, 113.9, 106.7, 52.7.
8. 8. N2-N2- 치환된 5-플루오로-2Substituted 5-fluoro-2 HH -인다졸-6-카르복실산 메틸 에스테르　화합물 합성(화합물 82 - 84)-indazole-6-carboxylic acid methyl ester compound synthesis (compounds 82 - 84)
DMF(2ml)에서 5-플루오로-1H-인다졸-6-카르복실산 메틸 에스테르(화합물 81; 0.53 mmol), 알킬 브로마이드/클로라이드(0.58 mmol) 및 Cs2CO3(0.58 mmol)의 혼합물을 실온(rt)에서 2시간 동안 반응시켰다. 반응 완료 후 반응 혼합물을 물에 넣고 에틸아세테이트로 조산물(crude product)을 추출하였다. 용출물로 헥산:에틸아세테이트(3:1)를 이용한 컬럼 크로마토그래피로 N2 치환된 5-플루오로-인다졸 유도체(화합물 82 - 84)를 각각 분리하였다.A mixture of 5-fluoro-1 H -indazole-6-carboxylic acid methyl ester (Compound 81; 0.53 mmol), alkyl bromide/chloride (0.58 mmol) and Cs 2 CO 3 (0.58 mmol) in DMF (2 ml). was reacted at room temperature (rt) for 2 hours. After completion of the reaction, the reaction mixture was added to water and the crude product was extracted with ethyl acetate. N2 -substituted 5-fluoro-indazole derivatives (compounds 82 to 84) were separated by column chromatography using hexane:ethyl acetate (3:1) as an eluent.
1) 2-벤질-5-플루오로-2H-인다졸-6-카르복실산 메틸 에스테르[2-Benzyl-5-fluoro-2H-indazole-6-carboxylic acid methyl ester; 화합물 82]1) 2-Benzyl-5-fluoro- 2H -indazole-6-carboxylic acid methyl ester [2-Benzyl-5-fluoro- 2H -indazole-6-carboxylic acid methyl ester; Compound 82]
노란색 고체; 수율 55%, 1H NMR (500 MHz, CDCl3) δ 8.31 (d, J = 6.3 Hz, 1H), 7.77 (s, 1H), 7.30 - 7.24 (m, 3H), 7.21 - 7.15 (m, 3H), 5.51 (s, 2H), 3.85 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 165.3, 156.3, 145.1, 135.1, 129.1, 128.7, 128.1, 123.9, 123.2, 123.1, 120.0, 104.9, 58.1, 52.4.yellow solid; Yield 55%, 1 H NMR (500 MHz, CDCl 3 ) δ 8.31 (d, J = 6.3 Hz, 1H), 7.77 (s, 1H), 7.30 - 7.24 (m, 3H), 7.21 - 7.15 (m, 3H) ), 5.51 (s, 2H), 3.85 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 165.3, 156.3, 145.1, 135.1, 129.1, 128.7, 128.1, 123.9, 123.2, 123.1, 120.0, 104.9, 58.1, 52.4.
2) 2-(3-클로로벤질)-5-플루오로-2H-인다졸-6-카르복실산 메틸 에스테르[2-(3-Chlorobenzyl)-5-fluoro-2H-indazole-6-carboxylic acid methyl ester; 화합물 83]2) 2-(3-Chlorobenzyl)-5-fluoro- 2H -indazole-6-carboxylic acid methyl ester [2-(3-Chlorobenzyl)-5-fluoro- 2H- indazole-6-carboxylic acid methyl ester; Compound 83]
노란색 고체; 수율 35%, 1H NMR (500 MHz, CDCl3) δ 8.41 (d, J = 6.3 Hz, 1H), 7.91 (s, 1H), 7.35 - 7.26 (m, 4H), 7.16 (dt, J = 6.9, 1.5 Hz, 1H), 5.58 (s, 2H), 3.96 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 165.2, 145.2, 144.2, 136.0, 130.4, 128.9, 128.1, 126.1, 124.0, 123.9, 123.1, 122.0, 120.3, 120.3, 104.6, 57.4, 52.5.yellow solid; Yield 35%, 1H NMR (500 MHz, CDCl 3 ) δ 8.41 (d, J = 6.3 Hz, 1H), 7.91 (s, 1H), 7.35 - 7.26 (m, 4H), 7.16 (dt, J = 6.9) , 1.5 Hz, 1H), 5.58 (s, 2H), 3.96 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 165.2, 145.2, 144.2, 136.0, 130.4, 128.9, 128.1, 126.1, 124.0, 123.9, 123.1, 122.0, 120.3, 120.3, 104 .6, 57.4, 52.5.
3) 2-(3-메톡시벤질)-5-플루오로-2H-인다졸-6-카르복실산 메틸 에스테르[2-(3-Methoxybenzyl)-5-fluoro-2H-indazole-6-carboxylic acid methyl ester; 화합물 84]3) 2-(3-Methoxybenzyl)-5-fluoro- 2H -indazole-6-carboxylic acid methyl ester [2-(3-Methoxybenzyl)-5-fluoro- 2H -indazole-6- carboxylic acid methyl ester; Compound 84]
노란색 고체; 수율 32%, 1H NMR (500 MHz, CDCl3) δ 8.41 (d, J = 6.2 Hz, 1H), 7.88 (s, 1H), 7.35 - 7.24 (m, 2H), 6.88 (d, J = 8.2 Hz, 2H), 6.82 (s, 1H), 5.58 (s, 2H), 3.96 (s, 3H), 3.77 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 165.3, 160.1, 156.3, 145.0, 136.5, 130.2, 123.89, 123.87, 123.2, 123.0, 120.3, 120.0, 113.9, 104.6, 58.0, 55.3, 52.4.yellow solid; Yield 32%, 1 H NMR (500 MHz, CDCl 3 ) δ 8.41 (d, J = 6.2 Hz, 1H), 7.88 (s, 1H), 7.35 - 7.24 (m, 2H), 6.88 (d, J = 8.2 Hz, 2H), 6.82 (s, 1H), 5.58 (s, 2H), 3.96 (s, 3H), 3.77 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 165.3, 160.1, 156.3, 145.0, 136.5, 130.2, 123.89, 123.87, 123.2, 123.0, 120.3, 120.0, 113.9, 104.6, 5 8.0, 55.3, 52.4.
9. 9. N2N2 치환된 5-플루오로-2 Substituted 5-fluoro-2 HH -인다졸-6-카르복실산　화합물 합성(화합물 85 - 87)-indazole-6-carboxylic acid compound synthesis (compounds 85 - 87)
N2 치환된 5-플루오로-2H-인다졸-6-카르복실산 메틸 에스테르(화합물 82-84, 0.34 mmol)을 메탄올(1 ml)과 THF(1 ml)에서 용해시키고, 2N NaOH 용액(0.5 ml)을 천천히 첨가하였다. 반응혼합물을 실온에서 2시간 동안 교반한 후, 물에 넣고 2N HCl로 중화시킨 후 침전물을 여과하고 건조하여 카르복실산 유도체(화합물 85 - 87)를 얻었다. N2- substituted 5-fluoro- 2H -indazole-6-carboxylic acid methyl ester (compound 82-84, 0.34 mmol) was dissolved in methanol (1 ml) and THF (1 ml) and added to 2N NaOH solution ( 0.5 ml) was added slowly. The reaction mixture was stirred at room temperature for 2 hours, added to water, neutralized with 2N HCl, and the precipitate was filtered and dried to obtain carboxylic acid derivatives (compounds 85 - 87).
1) 2-벤질-5-플루오로-2H-인다졸-6-카르복실산[2-Benzyl-5-fluoro-2H-indazole-6-carboxylic acid; 화합물 85]1) 2-Benzyl-5-fluoro-2 H -indazole-6-carboxylic acid [2-Benzyl-5-fluoro-2 H -indazole-6-carboxylic acid; Compound 85]
노란색 고체; 수율 76%, 1H NMR (500 MHz, DMSO-d 6) δ 13.08 (s, 1H), 8.47 (s, 1H), 8.09 (d, J = 6.4 Hz, 1H), 7.48 (d, J = 11.5 Hz, 1H), 7.36 - 7.17 (m, 5H), 5.61 (s, 2H). 13C NMR (125 MHz, DMSO-d 6) δ 166.0, 156.7, 144.9, 136.9, 129.1, 128.53, 128.51, 125.3, 122.9, 122.8, 120.8, 105.7, 57.2.yellow solid; Yield 76%, 1H NMR (500 MHz, DMSO- d 6 ) δ 13.08 (s, 1H), 8.47 (s, 1H), 8.09 (d, J = 6.4 Hz, 1H), 7.48 (d, J = 11.5) Hz, 1H), 7.36 - 7.17 (m, 5H), 5.61 (s, 2H). 13 C NMR (125 MHz, DMSO- d 6 ) δ 166.0, 156.7, 144.9, 136.9, 129.1, 128.53, 128.51, 125.3, 122.9, 122.8, 120.8, 105.7, 57.2.
2)　2-(3-클로로벤질)-5-플루오로-2H-인다졸-6-카르복실산[2-(3-Chlorobenzyl)-5-fluoro-2H-indazole-6-carboxylic acid; 화합물 86]2) 2-(3-Chlorobenzyl)-5-fluoro- 2H -indazole-6-carboxylic acid [2-(3-Chlorobenzyl)-5-fluoro- 2H -indazole-6-carboxylic acid; Compound 86]
흰색 고체; 수율 65%, 1H NMR (500 MHz, MeOD) δ 8.43 - 8.22 (m, 2H), 7.49 &#8211; 7.19 (m, 5H), 5.67 (s, 2H). white solid; Yield 65%, 1 H NMR (500 MHz, MeOD) δ 8.43 - 8.22 (m, 2H), 7.49 &#8211; 7.19 (m, 5H), 5.67 (s, 2H).
3) 2-(3_메톡시벤질)-5-플루오로-2H-인다졸-6-카르복실산[2-(3-Methoxybenzyl)-5-fluoro-2H-indazole-6-carboxylic acid; 화합물 87]3) 2-(3-Methoxybenzyl)-5-fluoro- 2H -indazole-6-carboxylic acid [2-(3-Methoxybenzyl)-5-fluoro- 2H -indazole-6-carboxylic acid ; Compound 87]
흰색 고체; 수율 99%, 1H NMR (500 MHz, MeOD) δ 8.32 (s, 1H), 8.29 (d, J = 6.3 Hz, 1H), 7.43 (dd, J = 11.2, 1.7 Hz, 1H), 7.27 (t, J = 7.8 Hz, 1H), 6.93 -　6.85 (m, 3H), 5.63 (s, 2H), 3.76 (s, 3H). 13C NMR (125 MHz, MeOD) δ 166.4, 160.1, 156.2, 144.8, 137.2, 129.6, 124.6, 123.1, 122.4, 122.4, 119.8, 113.4, 104.6, 57.1, 54.3.white solid; Yield 99%, 1H NMR (500 MHz, MeOD) δ 8.32 (s, 1H), 8.29 (d, J = 6.3 Hz, 1H), 7.43 (dd, J = 11.2, 1.7 Hz, 1H), 7.27 (t , J = 7.8 Hz, 1H), 6.93 - 6.85 (m, 3H), 5.63 (s, 2H), 3.76 (s, 3H). 13 C NMR (125 MHz, MeOD) δ 166.4, 160.1, 156.2, 144.8, 137.2, 129.6, 124.6, 123.1, 122.4, 122.4, 119.8, 113.4, 104.6, 57.1, 54.3.
10. 10. N2N2 치환된 2-벤질-5-플루오로-2 Substituted 2-benzyl-5-fluoro-2 HH -인다졸-6-카르복실산　화합물 합성(화합물 88-90)-indazole-6-carboxylic acid compound synthesis (compound 88-90)
카르복실산 유도체(화합물 85 - 87; 0.27 mmol), 하이드록시아민 염산염(0.82 mmol), BOP(benzotriazol-l-yl-oxy-tris-(dimethylamino)phosphonium hexa-fluorophosphate; 0.41 mmol) 및 DIPEA(diisopropylethylamine; 0.82 mmol)의 혼합물을 DMSO(1 - 2 ml)에 첨가하고 실온에서 6-8 시간 동안 교반하였다. 반응혼합물을 물로 희석한 후 에틸아세테이트로 추출하였다. 용출액으로 클로로포름:메탄올(90:10)을 이용한 컬럼 크로마토그래피에 의해 생성물을 정제하였다.Carboxylic acid derivatives (compounds 85 - 87; 0.27 mmol), hydroxyamine hydrochloride (0.82 mmol), benzotriazol-l-yl-oxy-tris-(dimethylamino)phosphonium hexa-fluorophosphate (BOP; 0.41 mmol) and diisopropylethylamine (DIPEA) ; 0.82 mmol) was added to DMSO (1 - 2 ml) and stirred at room temperature for 6-8 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The product was purified by column chromatography using chloroform:methanol (90:10) as an eluent.
１) SPA3659[2-벤질-5-플루오로-2１) SPA3659 [2-benzyl-5-fluoro-2 HH -인다졸-6-카르복실산 하이드록시아마이드(2-Benzyl-5-fluoro-2-Indazole-6-carboxylic acid hydroxyamide (2-Benzyl-5-fluoro-2 HH -indazole-6-carboxylic acid hydroxyamide; 화합물 88)]-indazole-6-carboxylic acid hydroxyamide; Compound 88)]
갈색 고체; 수율 18%, 1H NMR (500 MHz, DMSO-d 6) δ 11.05 (s, 1H), 9.27 (s, 1H), 8.15 (s, 1H), 7.94 (d, J = 5.3 Hz, 1H), 7.65 (d, J = 10.0 Hz, 1H), 7.37 -　7.17 (m, 5H), 5.71 (s, 2H).brown solid; Yield 18%, 1H NMR (500 MHz, DMSO- d 6 ) δ 11.05 (s, 1H), 9.27 (s, 1H), 8.15 (s, 1H), 7.94 (d, J = 5.3 Hz, 1H), 7.65 (d, J = 10.0 Hz, 1H), 7.37 - 7.17 (m, 5H), 5.71 (s, 2H).
２) SPA3662[2-(3-클로로벤질)-5-플루오로-2２) SPA3662[2-(3-chlorobenzyl)-5-fluoro-2 HH -인다졸-6-카르복실산 하이드록시아마이드(2-(3-Chlorobenzyl)-5-fluoro-2-Indazole-6-carboxylic acid hydroxyamide (2-(3-Chlorobenzyl)-5-fluoro-2 HH -indazole-6-carboxylic acid hydroxyamide; 화합물　89)]-indazole-6-carboxylic acid hydroxyamide; Compound 89)]
연한 노란색 고체; 수율 24%, 1H NMR (500 MHz, MeOD) δ 8.37 (s, 1H), 7.92 (d, J = 5.9 Hz, 1H), 7.46 (d, J = 10.6 Hz, 1H), 7.35 - 7.30 (m, 3H), 7.28 - 7.22 (m, 1H), 5.65 (s, 2H). 13C NMR (125 MHz, MeOD) δ 163.8, 155.9, 145.1, 138.2, 134.3, 130.1, 128.1, 127.6, 126.0, 124.9, 123.1, 122.2, 119.4, 104.4, 56.3.Light yellow solid; Yield 24%, 1H NMR (500 MHz, MeOD) δ 8.37 (s, 1H), 7.92 (d, J = 5.9 Hz, 1H), 7.46 (d, J = 10.6 Hz, 1H), 7.35 - 7.30 (m , 3H), 7.28 - 7.22 (m, 1H), 5.65 (s, 2H). 13 C NMR (125 MHz, MEOD) Δ 163.8, 155.9, 145.1, 138.2, 134.3, 130.1, 128.1, 127.6, 126.0, 124.9, 123.1, 122.2, 119.4, 104.4, 56.3.
３) SPA3663[2-(3-메톡시벤질)-5-플루오로-2３) SPA3663[2-(3-methoxybenzyl)-5-fluoro-2 HH -인다졸-6-카르복실산 하이드록시아마이드(2-(3-Methoxybenzyl)-5-fluoro-2-Indazole-6-carboxylic acid hydroxyamide (2-(3-Methoxybenzyl)-5-fluoro-2 HH -indazole-6-carboxylic acid hydroxyamide; 화합물　90)]-indazole-6-carboxylic acid hydroxyamide; Compound 90)]
갈색 고체; 수율 22%, 1H NMR (500 MHz, MeOD) δ 8.36 (s, 1H), 7.94 (d, J = 5.6 Hz, 1H), 7.48 (d, J = 10.5 Hz, 1H), 7.35 - 7.24 (m, 1H), 6.97 - 6.87 (m, 3H), 5.64 (s, 2H), 3.78 (s, 3H).brown solid; Yield 22%, 1H NMR (500 MHz, MeOD) δ 8.36 (s, 1H), 7.94 (d, J = 5.6 Hz, 1H), 7.48 (d, J = 10.5 Hz, 1H), 7.35 - 7.24 (m , 1H), 6.97 - 6.87 (m, 3H), 5.64 (s, 2H), 3.78 (s, 3H).
<실험예 1> 합성 화합물의 HDAC6 및 HDAC8 억제 활성 평가<Experimental Example 1> Evaluation of HDAC6 and HDAC8 inhibitory activity of synthetic compounds
1) 기질의 탈아세틸화 과정 및 현상과정1) Substrate deacetylation process and development process
HDAC 효소가 없는 대조군 웰을 제외한 반응 플레이트의 각 웰에 2X HDAC 효소를 분주하고, 효소가 없는 대조군 웰에는 버퍼를 분주하였다. Acoustic 기술(Echo550, nanoliter range)을 사용하여 100% DMSO에 용해시킨 화합물을 효소 혼합물에 넣고, 스핀다운하고 실온에서 10분 동안 예비 배양하였다. 모든 반응 웰에 2X 기질 혼합물(Fluorogenic HDAC 기질)을 넣고 반응을 시작한 후, 스핀다운 하였다. HDAC6는 1시간, HDAC8의 경우 2시간 동안 30℃에서 배양하였다.2X HDAC enzyme was dispensed into each well of the reaction plate except for the control well without HDAC enzyme, and buffer was dispensed into the control well without enzyme. Using Acoustic technology (Echo550, nanoliter range), compounds dissolved in 100% DMSO were added to the enzyme mixture, spun down, and preincubated for 10 minutes at room temperature. 2X substrate mixture (Fluorogenic HDAC substrate) was added to all reaction wells, the reaction was started, and then spun down. HDAC6 was incubated at 30°C for 1 hour, and HDAC8 was incubated for 2 hours.
이후 트리코스타틴 A와 함께 현상액(developer)을 추가하여 반응을 중지하여 형광발색하였다. Envision(Ex/Em=360/460nm)으로 5분 간격으로 20분 동안 동력학적인 측정을 수행하였으며, 현상이 안정기에 도달한 후 분석을 위해 종말점 판독값을 취하였다.Afterwards, a developer was added along with trichostatin A to stop the reaction and produce fluorescence. Kinetic measurements were performed with Envision (Ex/Em=360/460 nm) at 5-minute intervals for 20 minutes, and endpoint readings were taken for analysis after the phenomenon reached a plateau.
2) 합성 화합물의 HDAC6 및 HDAC8 억제 활성2) HDAC6 and HDAC8 inhibitory activity of synthetic compounds
합성 화합물의 HDAC6와 HDAC8에 대한 억제 활성을 검토한 결과, SPA3602, 3603, 3606, 3608, 3610, 3612, 3614, 3616, 3618, 3620, 3621, 3622, 3624, 3626, 3628, 3630, 3632, 3634, 3636, 3638, 3640, 3642, 3644, 3646 및 3648은 다음 표와 같이 1.3 내지 29.3 nM 범위의 IC50을 나타내면서 HDAC6에 대한 효과적인 억제 활성을 나타내었으며, HDAC8에 대해서는 500.3 내지 8392.0 nM 법위의 IC50로 상대적으로 낮은 활성을 보여 HDAC6 선택성을 확인하였다. 이러한 결과로부터 N2-치환된 유도체는 HDAC6에 대한 선택적이면서 효과적인 저해제인 것을 확인할 수 있었고, 암질환, 염증질환, 자가면역질환 및 섬유화 질환 등 다양한 질환의 치료제로서 활용될 수 있다.As a result of examining the inhibitory activity of synthetic compounds against HDAC6 and HDAC8, SPA3602, 3603, 3606, 3608, 3610, 3612, 3614, 3616, 3618, 3620, 3621, 3622, 3624, 3626, 3628, 3630, 3632, 3634 , 3636, 3638, 3640, 3642, 3644, 3646 and 3648 showed effective inhibitory activity against HDAC6, with IC 50 in the range of 1.3 to 29.3 nM as shown in the following table, and for HDAC8, IC 50 in the range of 500.3 to 8392.0 nM. HDAC6 selectivity was confirmed by showing relatively low activity. From these results, it was confirmed that the N2 -substituted derivative is a selective and effective inhibitor of HDAC6, and can be used as a treatment for various diseases such as cancer diseases, inflammatory diseases, autoimmune diseases, and fibrotic diseases.
연번serial number 화합물 NO.Compound NO. SPA NoSPA No 구조structure HDAC6 IC50
(nM)HDAC6 IC 50
(nM) 		HDAC8 IC50
(nM)HDAC8 IC 50
(nM)
1One 5050 SPA3602SPA3602
Figure PCTKR2023003562-appb-img-000007
Figure PCTKR2023003562-appb-img-000007
 		2.62.6 1320.01320.0
22 5151 SPA3603SPA3603
Figure PCTKR2023003562-appb-img-000008
Figure PCTKR2023003562-appb-img-000008
 		5.45.4 765.0765.0
33 5252 SPA3606SPA3606
Figure PCTKR2023003562-appb-img-000009
Figure PCTKR2023003562-appb-img-000009
 		7.47.4 699.3699.3
44 5353 SPA3608SPA3608
Figure PCTKR2023003562-appb-img-000010
Figure PCTKR2023003562-appb-img-000010
 		5.95.9 932.5932.5
55 5454 SPA3610SPA3610
Figure PCTKR2023003562-appb-img-000011
Figure PCTKR2023003562-appb-img-000011
 		2.72.7 775.6775.6
66 5555 SPA3612SPA3612
Figure PCTKR2023003562-appb-img-000012
Figure PCTKR2023003562-appb-img-000012
 		3.43.4 592.7592.7
77 5656 SPA3614SPA3614
Figure PCTKR2023003562-appb-img-000013
Figure PCTKR2023003562-appb-img-000013
 		4.44.4 1016.01016.0
88 5757 SPA3616SPA3616
Figure PCTKR2023003562-appb-img-000014
Figure PCTKR2023003562-appb-img-000014
 		5.55.5 1069.01069.0
99 5858 SPA3618SPA3618
Figure PCTKR2023003562-appb-img-000015
Figure PCTKR2023003562-appb-img-000015
 		4.24.2 870.3870.3
1010 5959 SPA3620SPA3620
Figure PCTKR2023003562-appb-img-000016
Figure PCTKR2023003562-appb-img-000016
 		4.04.0 1167.01167.0
1111 6060 SPA3622SPA3622
Figure PCTKR2023003562-appb-img-000017
Figure PCTKR2023003562-appb-img-000017
 		4.74.7 1101.01101.0
1212 6161 SPA3624SPA3624
Figure PCTKR2023003562-appb-img-000018
Figure PCTKR2023003562-appb-img-000018
 		3.93.9 877.2877.2
연번serial number 화합물 NO.Compound NO. SPA NoSPA No 구조structure HDAC6 IC50
(nM)HDAC6 IC 50
(nM) 		HDAC8 IC50
(nM)HDAC8 IC 50
(nM)
1313 6262 SPA3626SPA3626
Figure PCTKR2023003562-appb-img-000019
Figure PCTKR2023003562-appb-img-000019
 		4.14.1 500.3500.3
1414 6363 SPA3628SPA3628
Figure PCTKR2023003562-appb-img-000020
Figure PCTKR2023003562-appb-img-000020
 		3.63.6 1289.01289.0
1515 6464 SPA3630SPA3630
Figure PCTKR2023003562-appb-img-000021
Figure PCTKR2023003562-appb-img-000021
 		29.329.3 2864.02864.0
1616 6565 SPA3632SPA3632
Figure PCTKR2023003562-appb-img-000022
Figure PCTKR2023003562-appb-img-000022
 		6.76.7 1520.01520.0
1717 6666 SPA3634SPA3634
Figure PCTKR2023003562-appb-img-000023
Figure PCTKR2023003562-appb-img-000023
 		1.81.8 1126.01126.0
1818 6767 SPA3636SPA3636
Figure PCTKR2023003562-appb-img-000024
Figure PCTKR2023003562-appb-img-000024
 		1.31.3 8392.08392.0
1919 6868 SPA3638SPA3638
Figure PCTKR2023003562-appb-img-000025
Figure PCTKR2023003562-appb-img-000025
 		3.33.3 738.0738.0
2020 6969 SPA3640SPA3640
Figure PCTKR2023003562-appb-img-000026
Figure PCTKR2023003562-appb-img-000026
 		3.03.0 598.2598.2
2121 7070 SPA3642SPA3642
Figure PCTKR2023003562-appb-img-000027
Figure PCTKR2023003562-appb-img-000027
 		1.81.8 966.9966.9
2222 7171 SPA3644SPA3644
Figure PCTKR2023003562-appb-img-000028
Figure PCTKR2023003562-appb-img-000028
 		13.513.5 2125.02125.0
2323 7272 SPA3646SPA3646
Figure PCTKR2023003562-appb-img-000029
Figure PCTKR2023003562-appb-img-000029
 		3.83.8 814.0814.0
2424 7373 SPA3648SPA3648
Figure PCTKR2023003562-appb-img-000030
Figure PCTKR2023003562-appb-img-000030
 		22.822.8 2005.02005.0
2525 7676 SPA3650SPA3650
Figure PCTKR2023003562-appb-img-000031
Figure PCTKR2023003562-appb-img-000031
 		-- --
2626 8888 SPA3659SPA3659
Figure PCTKR2023003562-appb-img-000032
Figure PCTKR2023003562-appb-img-000032
 		74.374.3 3845.03845.0
2727 8989 SPA3662SPA3662
Figure PCTKR2023003562-appb-img-000033
Figure PCTKR2023003562-appb-img-000033
 		30.330.3 2374.02374.0
2828 9090 SPA3663SPA3663
Figure PCTKR2023003562-appb-img-000034
Figure PCTKR2023003562-appb-img-000034
 		75.475.4 2851.02851.0
하기에 본 발명에 따른 화합물 50(SPA3602)을 포함하는 조성물의 제제예를 설명하나, 본 발명은 이를 한정하고자 함이 아닌 단지 구체적으로 설명하고자 함이다.Below, a formulation example of a composition containing compound 50 (SPA3602) according to the present invention will be described, but the present invention is not intended to be limited, but merely explained in detail.
<처방예 1> 약학조성물의 처방예<Prescription Example 1> Prescription example of pharmaceutical composition
<처방예 1-1> 산제의 제조<Prescription Example 1-1> Preparation of powder
화합물 50(SPA3602) 20 mg, 유당 100 mg 및 탈크 10 mg을 혼합하고 기밀포에 충진하여 산제를 제조하였다.A powder was prepared by mixing 20 mg of compound 50 (SPA3602), 100 mg of lactose, and 10 mg of talc and filling it in an airtight bubble.
<처방예 1-2> 정제의 제조<Prescription Example 1-2> Preparation of tablets
화합물 50(SPA3602) 10 mg, 옥수수전분 100 mg, 유당 100 mg 및 스테아린산 마그네슘 2 mg을 혼합한 후 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조하였다.Tablets were prepared by mixing 10 mg of compound 50 (SPA3602), 100 mg of corn starch, 100 mg of lactose, and 2 mg of magnesium stearate and compressing them according to a conventional tablet manufacturing method.
<처방예 1-3> 캅셀제의 제조<Prescription Example 1-3> Preparation of capsules
화합물 50(SPA3602) 10 mg, 옥수수전분 100 mg, 유당 100 mg 및 스테아린산 마그네슘 2 mg을 혼합한 후 통상의 캡슐제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 충전하여 캡슐제를 제조하였다.A capsule was prepared by mixing 10 mg of Compound 50 (SPA3602), 100 mg of corn starch, 100 mg of lactose, and 2 mg of magnesium stearate, mixing the above ingredients according to a typical capsule manufacturing method, and filling a gelatin capsule.
<처방예 1-4> 주사제의 제조<Prescription Example 1-4> Preparation of injections
화합물 50(SPA3602) 10 mg, 주사용 멸균 증류수 적량 및 pH 조절제 적량을 혼합한 후 통상의 주사제의 제조방법에 따라 1 앰플당(2 ㎖) 상기의 성분 함량으로 제조하였다.After mixing 10 mg of compound 50 (SPA3602), an appropriate amount of sterilized distilled water for injection, and an appropriate amount of a pH adjuster, the mixture was prepared with the above ingredient content per ampoule (2 ml) according to a conventional injection preparation method.
<처방예 2> 건강보조식품<Prescription Example 2> Health supplement
<처방예 2-1> 건강식품의 제조<Prescription Example 2-1> Manufacturing of health food
화합물 50(SPA3602) 1 ㎎, 비타민 혼합물 적량(비타민 A 아세테이트 70 ㎍, 비타민 E 1.0 ㎎, 비타민 B1 0.13 ㎎, 비타민 B2 0.15 ㎎, 비타민 B6 0.5 ㎎, 비타민 B12 0.2 ㎍, 비타민 C10 ㎎, 비오틴 10 ㎍, 니코틴산아미드 1.7 ㎎, 엽산 50 ㎍, 판토텐산 칼슘 0.5 ㎎) 및 무기질 혼합물 적량(황산 제1철 1.75 ㎎, 산화아연 0.82 ㎎, 탄산마그네슘 25.3 ㎎, 제1인산칼륨 15 ㎎, 제2인산칼슘 55 ㎎, 구연산칼륨 90 ㎎, 탄산칼슘 100 ㎎, 염화마그네슘 24.8 ㎎)을 혼합한 다음 과립을 제조하고 통상의 방법에 따라 건강식품을 제조하였다.Compound 50 (SPA3602) 1 mg, appropriate amount of vitamin mixture (vitamin A acetate 70 μg, vitamin E 1.0 mg, vitamin B1 0.13 mg, vitamin B2 0.15 mg, vitamin B6 0.5 mg, vitamin B12 0.2 μg, vitamin C10 mg, biotin 10 μg , nicotinic acid amide 1.7 mg, folic acid 50 ㎍, calcium pantothenate 0.5 mg) and mineral mixture (ferrous sulfate 1.75 mg, zinc oxide 0.82 mg, magnesium carbonate 25.3 mg, monobasic potassium phosphate 15 mg, dicalcium phosphate 55 mg) , 90 mg of potassium citrate, 100 mg of calcium carbonate, and 24.8 mg of magnesium chloride) were mixed to prepare granules, and health food was prepared according to a conventional method.
<처방예 2-2> 건강음료의 제조<Prescription Example 2-2> Manufacturing of health drinks
화합물 50(SPA3602) 1 ㎎, 구연산 1000 ㎎, 올리고당 100 g, 매실농축액 2 g, 타우린 1 g 및 정제수를 가하여 전체 900 ㎖가 되도록 하며, 통상의 건강음료 제조방법에 따라 상기의 성분을 혼합한 다음, 약 1시간 동안 85℃에서 교반 가열한 후, 만들어진 용액을 여과하여 멸균된 2 L 용기에 취득하여 밀봉 멸균한 뒤 냉장 보관하였다. Add 1 mg of Compound 50 (SPA3602), 1000 mg of citric acid, 100 g of oligosaccharide, 2 g of plum concentrate, 1 g of taurine and purified water to make a total of 900 ml, and mix the above ingredients according to a normal health drink manufacturing method. After stirring and heating at 85°C for about 1 hour, the resulting solution was filtered, placed in a sterilized 2 L container, sealed, sterilized, and stored in the refrigerator.
이상으로 본 발명의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적 기술은 단지 바람직한 실시예일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.As the specific parts of the present invention have been described in detail above, it is clear to those skilled in the art that these specific techniques are merely preferred embodiments and do not limit the scope of the present invention. will be. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

Claims (19)

  1. 하기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염에서 선택된 화합물:A compound selected from the compounds represented by the following formula (1) or pharmaceutically acceptable salts thereof:
    [화학식 1][Formula 1]
    Figure PCTKR2023003562-appb-img-000035
    Figure PCTKR2023003562-appb-img-000035
    상기 화학식 1에서, In Formula 1,
    X는 수소, 불소, 염소 또는 브롬에서 선택되고,X is selected from hydrogen, fluorine, chlorine or bromine,
    A는 치환되거나 치환되지 않은 페닐, 나프틸 또는 헤테로고리 화합물에서 선택되고,A is selected from substituted or unsubstituted phenyl, naphthyl or heterocyclic compounds,
    상기 치환은 (C1~C10)알킬, (C1~C10)알콕시, 할로, 다이플루오로메틸, 트리플루오로메틸, 하이드록시, 시아노, 나이트로, 페닐, 벤질옥시 또는 페녹시에서 선택된 하나 이상의 치환기로 치환되고, The substitution is one or more substituents selected from (C1~C10)alkyl, (C1~C10)alkoxy, halo, difluoromethyl, trifluoromethyl, hydroxy, cyano, nitro, phenyl, benzyloxy, or phenoxy. is replaced with,
    상기 헤테로고리 화합물은 5환 또는 6환의 헤테로아릴 화합물이며,The heterocyclic compound is a 5- or 6-ring heteroaryl compound,
    n은 1 내지 3의 정수임.n is an integer from 1 to 3.
  2. 청구항 1에 있어서, 상기 헤테로고리 화합물은 티오펜, 퓨란, 피로졸, 피리딘, 피란, 옥사진, 티아진, 피리미딘 및 피페라진으로 이루어진 군에서 선택된 것을 특징으로 하는 화합물.The compound according to claim 1, wherein the heterocyclic compound is selected from the group consisting of thiophene, furan, pyrazole, pyridine, pyran, oxazine, thiazine, pyrimidine, and piperazine.
  3. 청구항 1 또는 청구항 2에 있어서, 상기 화합물은 하기 화학식 1-1로 표시되는 화합물인 것을 특징으로 하는 화합물:The compound according to claim 1 or 2, wherein the compound is represented by the following formula 1-1:
    [화학식 1-1][Formula 1-1]
    Figure PCTKR2023003562-appb-img-000036
    Figure PCTKR2023003562-appb-img-000036
    상기 화학식 1-1에서,In Formula 1-1,
    X는 수소 또는 불소이고,X is hydrogen or fluorine,
    A는 페닐, 나프틸 또는 피리미딜에서 선택되고,A is selected from phenyl, naphthyl or pyrimidyl,
    R1 및 R2는 각각 동일하거나 다를 수 있고, 수소, (C1~C4)알킬, (C1~C4)알콕시, 할로, 다이플루오로메틸, 트리플루오로메틸, 페닐, 벤질옥시 또는 페녹시에서 선택되며, R 1 and R 2 may each be the same or different and are selected from hydrogen, (C1~C4)alkyl, (C1~C4)alkoxy, halo, difluoromethyl, trifluoromethyl, phenyl, benzyloxy, or phenoxy. And
    n은 1 내지 3의 정수임.n is an integer from 1 to 3.
  4. 청구항 3에 있어서, 상기 화합물은 i) A는 페닐, 나프틸 또는 피리미딜에서 선택되고, R1은 수소, (C1~C4)알킬, (C1~C4)알콕시, 할로, 다이플루오로메틸, 트리플루오로메틸, 페닐, 벤질옥시 또는 페녹시에서 선택되며, R2는 수소, (C1~C4)알콕시 또는 할로에서 선택되며, n은 1 내지 2의 정수인 것을 특징으로 하는 화합물.The method of claim 3, wherein the compound is i) A is selected from phenyl, naphthyl or pyrimidyl, and R 1 is hydrogen, (C1~C4)alkyl, (C1~C4)alkoxy, halo, difluoromethyl, tri. A compound selected from fluoromethyl, phenyl, benzyloxy or phenoxy, R 2 is selected from hydrogen, (C1-C4) alkoxy or halo, and n is an integer of 1 to 2.
  5. 청구항 1에 있어서, 상기 화합물은 The method of claim 1, wherein the compound is
    2-벤질-2H-인다졸-6-카르복실산 하이드록시아마이드(2-Benzyl-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 50); 2-Benzyl-2 H -indazole-6-carboxylic acid hydroxyamide (Compound 50 ) ;
    2-(4-메톡시벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(4-Methoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 51);2-(4 - Methoxybenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 51);
    2-(4-메틸벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(4-Methylbenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 52);2-(4 - Methylbenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 52);
    2-(4-플루오로벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(4-Fluorobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 53);2-(4 - Fluorobenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 53);
    2-(4-클로로벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(4-Chlorobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 54);2-(4 - Chlorobenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 54);
    2-(4-브로모벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(4-Bromobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 55);2-(4 - Bromobenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 55);
    2-(3-트리플루오로메톡시벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(3-Trifluoromethoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 56);2-(3 - Trifluoromethoxybenzyl) -2H- indazole-6-carboxylic acid hydroxyamide (Compound 56);
    2-(4-트리플루오로메톡시벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(4-Trifluoromethoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 57);2-(4 - Trifluoromethoxybenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 57);
    2-나프탈렌-2-일메틸-2H-인다졸-6-카르복실산 하이드록시아마이드(2-Naphthalen-2-ylmethyl-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 58);2-Naphthalen-2-ylmethyl- 2H -indazole-6-carboxylic acid hydroxyamide (Compound 58 ) ;
    2-페네틸-2H-인다졸-6-카르복실산 하이드록시아마이드(2-Phenethyl-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 59);2 - Phenethyl-2 H- indazole-6-carboxylic acid hydroxyamide (Compound 59);
    2-(2-4-메톡시페닐에틸)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(2-4-Methoxyphenylethyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 60);2-(2-4 - Methoxyphenylethyl) -2H -indazole-6-carboxylic acid hydroxyamide; compound 60);
    2-(3,5-다이플로오로벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(3,5-Difluorobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 61);2-(3,5-difluorobenzyl)-2 H -indazole-6-carboxylic acid hydroxyamide (2-(3,5-Difluorobenzyl)-2 H -indazole-6-carboxylic acid hydroxyamide; compound 61);
    2-(4-다이플루오로메톡시벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(4-Difluoromethoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 62);2-(4 - difluoromethoxybenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 62);
    2-바이페닐-4-일메틸-2H-인다졸-6-카르복실산 하이드록시아마이드(2-Biphenyl-4-ylmethyl-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 63);2-Biphenyl-4-ylmethyl- 2H -indazole-6-carboxylic acid hydroxyamide (Compound 63 ) ;
    2-(4-아이소프로필벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(4-Isopropylbenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 64);2-(4 - Isopropylbenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 64);
    2-(2-(4-플루오로페닐)에틸)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(2-(4-Fluorophenyl)ethyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 65);2-(2-(4-Fluorophenyl)ethyl) -2H -indazole-6-carboxylic acid hydroxyamide (2-(2-(4-Fluorophenyl)ethyl)-2H - indazole-6- carboxylic acid hydroxyamide; compound 65);
    2-(3-플루오로벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(3-Fluorobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 66);2-(3 - Fluorobenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 66);
    2-(3-클로로벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(3-Chlorobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 67);2-(3 - Chlorobenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 67);
    2-(3-트리플루오로메틸벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(3-Trifluoromethylbenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 68);2-(3 - Trifluoromethylbenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 68);
    2-(4-트리플루오로메틸벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(4-Trifluoromethylbenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 69);2-(4 - Trifluoromethylbenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 69);
    2-(3-메톡시벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(3-Methoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 70);2-(3 - Methoxybenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 70);
    2-(3-벤질옥시벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(3-Benzyloxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 71);2-(3 - Benzyloxybenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 71);
    2-(3,5-다이메톡시벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(3,5-Dimethoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 72)2-(3,5-dimethoxybenzyl)-2 H -indazole-6-carboxylic acid hydroxyamide (2-(3,5-Dimethoxybenzyl)-2 H -indazole-6-carboxylic acid hydroxyamide; compound 72)
    2-(3-페녹시벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(3-Phenoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 73);2-(3 - Phenoxybenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 73);
    2-피리딘-3-일메틸-2H-인다졸-6-카르복실산 하이드록시아마이드(2-Pyridin-3-ylmethyl-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 76);2-Pyridin-3-ylmethyl - 2H -indazole-6-carboxylic acid hydroxyamide (Compound 76);
    2-벤질-5-플루오로-2H-인다졸-6-카르복실산 하이드록시아마이드(2-Benzyl-5-fluoro-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 88);2-Benzyl-5-fluoro- 2H -indazole-6-carboxylic acid hydroxyamide (Compound 88 );
    2-(3-클로로벤질)-5-플루오로-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(3-Chlorobenzyl)-5-fluoro-2H-indazole-6-carboxylic acid hydroxyamide; 화합물　89); 및2- ( 3-Chlorobenzyl)-5-fluoro- 2H -indazole-6-carboxylic acid hydroxyamide; compound 89); and
    2-(3-메톡시벤질)-5-플루오로-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(3-Methoxybenzyl)-5-fluoro-2H-indazole-6-carboxylic acid hydroxyamide; 화합물　90);로 이루어진 군에서 선택된 것을 특징으로 하는 화합물.2-(3-Methoxybenzyl)-5-fluoro- 2H -indazole-6-carboxylic acid hydroxyamide (2-(3-Methoxybenzyl)-5-fluoro- 2H -indazole-6-carboxylic A compound characterized in that it is selected from the group consisting of acid hydroxyamide; compound 90);
  6. 청구항 1 또는 청구항 2에 있어서, 상기 화합물은 히스톤 탈아세틸화 효소6(Histone deacetylase 6; HDAC6)을 선택적으로 억제하는 것을 특징으로 하는 화합물.The compound according to claim 1 or 2, wherein the compound selectively inhibits histone deacetylase 6 (HDAC6).
  7. 청구항 1 또는 청구항 2에 따른 화합물 또는 이의 약제학적으로 허용가능한 염에서 선택된 화합물을 포함하는 히스톤 탈아세틸화 효소6(Histone deacetylase 6; HDAC6) 관련 질환 치료 또는 예방용 약학조성물.A pharmaceutical composition for the treatment or prevention of diseases related to histone deacetylase 6 (HDAC6), comprising a compound selected from the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof.
  8. 청구항 7에 있어서, 상기 화합물은 하기 화학식 1-1로 표시되는 화합물인 것을 특징으로 하는 약학조성물:The pharmaceutical composition according to claim 7, wherein the compound is a compound represented by the following formula 1-1:
    [화학식 1-1][Formula 1-1]
    Figure PCTKR2023003562-appb-img-000037
    Figure PCTKR2023003562-appb-img-000037
    상기 화학식 1-1에서, In Formula 1-1,
    X는 수소 또는 불소이고,X is hydrogen or fluorine,
    A는 페닐, 나프틸 또는 피리미딜에서 선택되고,A is selected from phenyl, naphthyl or pyrimidyl,
    R1 및 R2는 각각 동일하거나 다를 수 있고, 수소, (C1~C4)알킬, (C1~C4)알콕시, 할로, 다이플루오로메틸, 트리플루오로메틸, 페닐, 벤질옥시 또는 페녹시에서 선택되며, R 1 and R 2 may each be the same or different and are selected from hydrogen, (C1~C4)alkyl, (C1~C4)alkoxy, halo, difluoromethyl, trifluoromethyl, phenyl, benzyloxy, or phenoxy. And
    n은 1 내지 3의 정수임.n is an integer from 1 to 3.
  9. 청구항 7에 있어서, 상기 화합물은 i) A는 페닐, 나프틸 또는 피리미딜에서 선택되고, R1은 수소, (C1~C4)알킬, (C1~C4)알콕시, 할로, 다이플루오로메틸, 트리플루오로메틸, 페닐, 벤질옥시 또는 페녹시에서 선택되며, R2는 수소, (C1~C4)알콕시 또는 할로에서 선택되며, n은 1 내지 2의 정수인 것을 특징으로 하는 약학조성물.The method of claim 7, wherein the compound is i) A is selected from phenyl, naphthyl or pyrimidyl, and R 1 is hydrogen, (C1~C4)alkyl, (C1~C4)alkoxy, halo, difluoromethyl, tri. A pharmaceutical composition characterized in that it is selected from fluoromethyl, phenyl, benzyloxy or phenoxy, R 2 is selected from hydrogen, (C1-C4) alkoxy or halo, and n is an integer of 1 to 2.
  10. 청구항 7에 있어서, 상기 화합물은 The method of claim 7, wherein the compound is
    2-벤질-2H-인다졸-6-카르복실산 하이드록시아마이드(2-Benzyl-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 50); 2-Benzyl-2 H -indazole-6-carboxylic acid hydroxyamide (Compound 50 ) ;
    2-(4-메톡시벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(4-Methoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 51);2-(4 - Methoxybenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 51);
    2-(4-메틸벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(4-Methylbenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 52);2-(4 - Methylbenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 52);
    2-(4-플루오로벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(4-Fluorobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 53);2-(4 - Fluorobenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 53);
    2-(4-클로로벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(4-Chlorobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 54);2-(4 - Chlorobenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 54);
    2-(4-브로모벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(4-Bromobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 55);2-(4 - Bromobenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 55);
    2-(3-트리플루오로메톡시벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(3-Trifluoromethoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 56);2-(3 - Trifluoromethoxybenzyl) -2H- indazole-6-carboxylic acid hydroxyamide (Compound 56);
    2-(4-트리플루오로메톡시벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(4-Trifluoromethoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 57);2-(4 - Trifluoromethoxybenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 57);
    2-나프탈렌-2-일메틸-2H-인다졸-6-카르복실산 하이드록시아마이드(2-Naphthalen-2-ylmethyl-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 58);2-Naphthalen-2-ylmethyl- 2H -indazole-6-carboxylic acid hydroxyamide (Compound 58 ) ;
    2-페네틸-2H-인다졸-6-카르복실산 하이드록시아마이드(2-Phenethyl-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 59);2 - Phenethyl-2 H- indazole-6-carboxylic acid hydroxyamide (Compound 59);
    2-(2-4-메톡시페닐에틸)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(2-4-Methoxyphenylethyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 60);2-(2-4 - Methoxyphenylethyl) -2H -indazole-6-carboxylic acid hydroxyamide; compound 60);
    2-(3,5-다이플로오로벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(3,5-Difluorobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 61);2-(3,5-difluorobenzyl)-2 H -indazole-6-carboxylic acid hydroxyamide (2-(3,5-Difluorobenzyl)-2 H -indazole-6-carboxylic acid hydroxyamide; compound 61);
    2-(4-다이플루오로메톡시벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(4-Difluoromethoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 62);2-(4 - difluoromethoxybenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 62);
    2-바이페닐-4-일메틸-2H-인다졸-6-카르복실산 하이드록시아마이드(2-Biphenyl-4-ylmethyl-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 63);2-Biphenyl-4-ylmethyl- 2H -indazole-6-carboxylic acid hydroxyamide (Compound 63 ) ;
    2-(4-아이소프로필벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(4-Isopropylbenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 64);2-(4 - Isopropylbenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 64);
    2-(2-(4-플루오로페닐)에틸)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(2-(4-Fluorophenyl)ethyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 65);2-(2-(4-Fluorophenyl)ethyl) -2H -indazole-6-carboxylic acid hydroxyamide (2-(2-(4-Fluorophenyl)ethyl)-2H - indazole-6- carboxylic acid hydroxyamide; compound 65);
    2-(3-플루오로벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(3-Fluorobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 66);2-(3 - Fluorobenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 66);
    2-(3-클로로벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(3-Chlorobenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 67);2-(3 - Chlorobenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 67);
    2-(3-트리플루오로메틸벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(3-Trifluoromethylbenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 68);2-(3 - Trifluoromethylbenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 68);
    2-(4-트리플루오로메틸벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(4-Trifluoromethylbenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 69);2-(4 - Trifluoromethylbenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 69);
    2-(3-메톡시벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(3-Methoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 70);2-(3 - Methoxybenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 70);
    2-(3-벤질옥시벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(3-Benzyloxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 71);2-(3 - Benzyloxybenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 71);
    2-(3,5-다이메톡시벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(3,5-Dimethoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 72) 2-(3,5-dimethoxybenzyl)-2 H -indazole-6-carboxylic acid hydroxyamide (2-(3,5-Dimethoxybenzyl)-2 H -indazole-6-carboxylic acid hydroxyamide; compound 72)
    2-(3-페녹시벤질)-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(3-Phenoxybenzyl)-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 73);2-(3 - Phenoxybenzyl) -2H -indazole-6-carboxylic acid hydroxyamide (Compound 73);
    2-피리딘-3-일메틸-2H-인다졸-6-카르복실산 하이드록시아마이드(2-Pyridin-3-ylmethyl-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 76);2-Pyridin-3-ylmethyl - 2H -indazole-6-carboxylic acid hydroxyamide (Compound 76);
    2-벤질-5-플루오로-2H-인다졸-6-카르복실산 하이드록시아마이드(2-Benzyl-5-fluoro-2H-indazole-6-carboxylic acid hydroxyamide; 화합물 88);2-Benzyl-5-fluoro- 2H -indazole-6-carboxylic acid hydroxyamide (Compound 88 );
    2-(3-클로로벤질)-5-플루오로-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(3-Chlorobenzyl)-5-fluoro-2H-indazole-6-carboxylic acid hydroxyamide; 화합물　89); 및2- ( 3-Chlorobenzyl)-5-fluoro- 2H -indazole-6-carboxylic acid hydroxyamide; compound 89); and
    2-(3-메톡시벤질)-5-플루오로-2H-인다졸-6-카르복실산 하이드록시아마이드(2-(3-Methoxybenzyl)-5-fluoro-2H-indazole-6-carboxylic acid hydroxyamide; 화합물　90);로 이루어진 군에서 선택된 것을 특징으로 하는 약학조성물.2-(3-Methoxybenzyl)-5-fluoro- 2H -indazole-6-carboxylic acid hydroxyamide (2-(3-Methoxybenzyl)-5-fluoro- 2H -indazole-6-carboxylic A pharmaceutical composition selected from the group consisting of acid hydroxyamide; compound 90);
  11. 청구항 7에 있어서, 상기 히스톤 탈아세틸화 효소6(Histone deacetylase 6; HDAC6) 관련 질환은 암질환, 염증질환, 자가면역질환, 섬유화 질환 및 퇴행성질환으로 이루어진 군에서 선택된 것을 특징으로 하는 약학조성물. The pharmaceutical composition according to claim 7, wherein the histone deacetylase 6 (HDAC6)-related disease is selected from the group consisting of cancer disease, inflammatory disease, autoimmune disease, fibrotic disease, and degenerative disease.
  12. 청구항 11에 있어서, 상기 암질환은 결장암, 폐암, 신장암, 방광암, 간암, 흉선암, 난소암, 자궁경부암, 유방암, 대장암, 위암, 췌장암, 결장암, 복막 전이암, 피부암, 방광암, 전립선암, 골육종, 섬유성 종양, 뇌종양, 급성 림프구성 백혈병, 급성 골수성 백혈병, 림프종 및 신경모세포종으로 이루어지는 군으로부터 선택된 것을 특징으로 하는 약학조성물.The method of claim 11, wherein the cancer diseases include colon cancer, lung cancer, kidney cancer, bladder cancer, liver cancer, thymus cancer, ovarian cancer, cervical cancer, breast cancer, colon cancer, stomach cancer, pancreas cancer, colon cancer, peritoneal metastasis cancer, skin cancer, bladder cancer, and prostate cancer. , a pharmaceutical composition selected from the group consisting of osteosarcoma, fibrous tumor, brain tumor, acute lymphocytic leukemia, acute myeloid leukemia, lymphoma, and neuroblastoma.
  13. 청구항 11에 있어서, 상기 염증질환 또는 자가면역질환은 골관절염, 류마티스 관절염(Rheumatoid Arthritis), 피부염, 알레르기, 아토피, 천식, 건선, 결막염, 비염, 중이염, 인후염, 편도염, 폐렴, 위궤양, 위염, 크론병, 염증성 장질환(inflammatory bowel disease), 루푸스, 간염, 방광염, 간질성방광염, 신장염, 쇼그렌 증후군(sjogren's syndrome), 다발성 경화증, 하시모토 갑상선(Hashimoto thyroiditis), 다발성근염(polymyositis), 경피증(scleroderma), 아디슨병(Addison disease), 백반증(vitiligo), 악성빈혈(pernicious anemia), 낭섬유증(Cystic Fibrosis), 이식편대숙주질환(graft-versus-host disease), 이식거부질환, 자가면역성 당뇨(Autoimmune Diabetes), 당뇨 망막증(Diabetic retinopathy), 허혈-재관류 손상(Ischemia-reperfusion injury), 혈관성형술후 재협착(Post-angioplasty restenosis), 만성 폐색성 심장 질환(Chronic obstructive pulmonary disease; COPD), 그레이브병(Graves disease) 및 급성 및 만성 염증 질환으로 이루어지는 군으로부터 선택된 것을 특징으로 하는 약학조성물. The method of claim 11, wherein the inflammatory disease or autoimmune disease is osteoarthritis, rheumatoid arthritis, dermatitis, allergy, atopy, asthma, psoriasis, conjunctivitis, rhinitis, otitis media, pharyngitis, tonsillitis, pneumonia, gastric ulcer, gastritis, and Crohn's disease. , inflammatory bowel disease, lupus, hepatitis, cystitis, interstitial cystitis, nephritis, Sjogren's syndrome, multiple sclerosis, Hashimoto thyroiditis, polymyositis, scleroderma, Addison disease, vitiligo, pernicious anemia, Cystic Fibrosis, graft-versus-host disease, transplant rejection disease, autoimmune diabetes. , Diabetic retinopathy, Ischemia-reperfusion injury, Post-angioplasty restenosis, Chronic obstructive pulmonary disease (COPD), Graves disease ) and a pharmaceutical composition selected from the group consisting of acute and chronic inflammatory diseases.
  14. 청구항 11에 있어서, 상기 섬유화 질환은 폐섬유증, 신섬유증, 심장섬유증, 간섬유증, 경피증, 골격근 섬유증 및 당뇨성 섬유증으로 이루어진 군에서 선택된 것을 특징으로 하는 약학조성물.The pharmaceutical composition according to claim 11, wherein the fibrotic disease is selected from the group consisting of pulmonary fibrosis, renal fibrosis, cardiac fibrosis, liver fibrosis, scleroderma, skeletal muscle fibrosis, and diabetic fibrosis.
  15. 청구항 11에 있어서, 상기 퇴행성질환은 뇌졸중, 중풍, 기억력 상실, 기억력 손상, 치매, 건망증, 파킨슨병, 알츠하이머병, 피크(Pick)병, 크로이츠펠트-야콥 (Creutzfeld-Kacob)병, 헌팅턴병 및 루게릭병으로 이루어진 군에서 선택된 퇴행성 신경질환인 것을 특징으로 하는 약학조성물.The method of claim 11, wherein the degenerative diseases include stroke, paralysis, memory loss, memory impairment, dementia, amnesia, Parkinson's disease, Alzheimer's disease, Pick's disease, Creutzfeld-Jakob disease, Huntington's disease, and Lou Gehrig's disease. A pharmaceutical composition characterized in that it is a degenerative neurological disease selected from the group consisting of.
  16. 청구항 1 또는 청구항 2에 따른 화합물 또는 이의 약제학적으로 허용가능한 염에서 선택된 화합물을 포함하는 히스톤 탈아세틸화 효소6(Histone deacetylase 6; HDAC6) 관련 질환 개선 또는 예방용 건강기능식품.A health functional food for improving or preventing diseases related to histone deacetylase 6 (HDAC6), comprising a compound selected from the compounds according to claim 1 or 2 or pharmaceutically acceptable salts thereof.
  17. 청구항 1 또는 청구항 2에 따른 화합물 또는 이의 약제학적으로 허용가능한 염에서 선택된 화합물을 히스톤 탈아세틸화 효소6(Histone deacetylase 6; HDAC6) 관련 질환을 앓고 있는 대상체에 투여하는 단계를 포함하는 히스톤 탈아세틸화 효소6(Histone deacetylase 6; HDAC6) 관련 질환 치료방법.Histone deacetylation comprising administering a compound selected from the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof to a subject suffering from a disease related to histone deacetylase 6 (HDAC6). Treatment method for diseases related to enzyme 6 (Histone deacetylase 6; HDAC6).
  18. 청구항 1 또는 청구항 2에 따른 화합물 또는 이의 약제학적으로 허용가능한 염에서 선택된 화합물을 포함하는 히스톤 탈아세틸화 효소6(Histone deacetylase 6; HDAC6) 저해용 조성물.A composition for inhibiting histone deacetylase 6 (HDAC6) comprising a compound selected from the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof.
  19. 청구항 1 또는 청구항 2에 따른 화합물 또는 이의 약제학적으로 허용가능한 염에서 선택된 화합물을 처리하는 단계를 포함하는 히스톤 탈아세틸화 효소6(Histone deacetylase 6; HDAC6) 저해방법.A method of inhibiting histone deacetylase 6 (HDAC6) comprising treating a compound selected from the group of claims 1 or 2 or a pharmaceutically acceptable salt thereof.
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